Process and device for delivery of fluid by chemical reaction

ABSTRACT

Processes and devices for delivering a fluid by chemical reaction are disclosed. A chemical reaction is initiated in a reaction chamber to produce a gas, and the gas acts upon a piston to deliver the fluid. Preferred devices typically include an upper chamber, a lower chamber, a fluid chamber, a piston between the lower chamber and the fluid chamber, and a barrier between the upper chamber and the lower chamber. When the barrier is broken, reagents in the upper chamber and the lower chamber are mixed together to generate the gas.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNos. 61/713,236 and 61/713,250; both of which were filed Oct. 12, 2012and both of which are incorporated herein by reference as if reproducedin full below.

BACKGROUND

The present disclosure relates to processes and devices for parenteraldelivery of high-viscosity fluids, e.g., protein therapeutics, by achemical reaction that generates a gas.

Protein therapeutics is an emerging class of drug therapy that promisesto provide treatment for a broad range of diseases, such as autoimmunedisorders, cardiovascular diseases, and cancer. The dominant deliverymethod for protein therapeutics, particularly monoclonal antibodies, isthrough intravenous infusion, in which large volumes of dilute solutionsare delivered over time. Intravenous infusion usually requires thesupervision of a doctor or nurse and is performed in a clinical setting.This can be inconvenient for a patient, and so efforts are being made topermit the delivery of protein therapeutics at home. Desirably, aprotein therapeutic formulation can be administered using a syringe forsubcutaneous delivery instead of requiring intravenous administration.Subcutaneous injections are commonly administered by laypersons, forexample in the administration of insulin by diabetics.

Transitioning therapeutic protein formulations from intravenous deliveryto injection devices like syringes requires addressing challengesassociated with delivering high concentrations of high molecular weightmolecules in a manner that is easy, reliable, and causes minimal pain tothe patient. In this regard, while intravenous bags typically have avolume of 1 liter, the standard volume for a syringe ranges from 0.3milliliters up to 25 milliliters. Thus, depending on the drug, todeliver the same amount of therapeutic proteins, the concentration mayhave to increase by a factor of 40 or more. Also, injection therapy ismoving towards smaller needle diameters and faster delivery times forpurposes of patient comfort and compliance.

Delivery of protein therapeutics is also challenging because of the highviscosity associated with such therapeutic formulations, and the highforces needed to push such formulations through a parenteral device.Formulations with absolute viscosities above 40-60 centipoise (cP) arevery difficult to deliver by conventional spring driven auto-injectorsfor multiple reasons. Structurally, the footprint of a spring for theamount of pressure delivered is relatively large and fixed to specificshapes, which reduces flexibility of design for delivery devices. Next,auto-injectors are usually made of plastic parts. However, a largeamount of energy must be stored in the spring to reliably deliverhigh-viscosity fluids. This may cause damage to the plastic parts due tocreep, which is the tendency of the plastic part to permanently deformunder stress. An auto-injector typically operates by using the spring topush a needle-containing internal component towards an outer edge of thehousing of the syringe. There is risk of breaking the syringe when theinternal component impacts the housing, due to the high applied forceneeded to inject a high-viscosity fluid. Also, the sound associated withthe impact can cause patient anxiety, reducing future compliance. Thegenerated pressure versus time profile of such a spring drivenauto-injector cannot be readily modified, which prevents users from finetuning pressure to meet their delivery needs.

It would be desirable to provide processes and devices by which ahigh-viscosity fluid could be self-administered in a reasonable time andwith a limited injection space. These processes and devices could beused to deliver high-concentration protein, or other high viscositypharmaceutical formulations.

SUMMARY

Disclosed in various embodiments are processes and devices for deliveryof a high-viscosity fluid using a gas-generating chemical reaction.Generally, one or more reagents are reacted to generate a gas. The gasis used to push a piston inside a syringe, delivering the contents ofthe syringe to the patient/user.

Disclosed in some embodiments is a device for delivering a fluid bychemical reaction, comprising: a reagent chamber having a plunger at anupper end and a one-way valve at a lower end, the one-way valvepermitting exit from the reagent chamber; a reaction chamber having theone-way valve at an upper end and a piston at a lower end; and a fluidchamber having the piston at an upper end, wherein the piston moves inresponse to pressure generated in the reaction chamber such that thevolume of the reaction chamber increases and the volume of the fluidchamber decreases.

The reaction chamber may have a volume of at most 1 cm³. The fluidchamber may contain a high-viscosity fluid having an absolute viscosityof from about 5 centipoise to about 1000 centipoise, or a viscosity ofat least 40 centipoise. The reagent chamber may contain a solvent and abicarbonate powder dissolved in the solvent. The solvent can comprisewater. The reaction chamber may contain a dry acid powder and a releaseagent. In particular embodiments, the acid powder is citrate and therelease agent is sodium chloride. Alternatively, the reaction chambercan contain at least one or at least two chemical reagents that reactwith each other to generate a gas. Separately, the reaction chamber mayfurther comprise a release agent.

In some alternative embodiments, an upper chamber may contain a solvent.The lower chamber may contain at least two chemical reagents that reactwith each other to generate a gas. The lower chamber may contain abicarbonate powder and an acid powder.

The piston of the device may be formed from a push surface at the lowerend of the reaction chamber, a stopper at the upper end of the fluidchamber, and a rod connecting the push surface and the stopper.

A plunger may include a thumbrest, as well as a pressure lock thatcooperates with the upper chamber to lock the plunger in place afterbeing depressed. The pressure lock can be proximate the thumbrest andcooperate with an upper surface of the upper chamber.

The lower chamber may be defined by the one-way valve, a continuoussidewall, and the piston, the one-way valve and the sidewall being fixedrelative to each other such that the volume of the lower chamber changesonly through movement of the piston.

In particular embodiments, the upper chamber, the lower chamber, and thefluid chamber are cylindrical and are coaxial. In others, the upperchamber, the lower chamber, and the fluid chamber are separate piecesthat are joined together to make the device. The one-way valve can feeda balloon in the lower chamber, the balloon pushing the piston.Sometimes, either the upper chamber or the lower chamber contains anencapsulated reagent.

Also described in various embodiments is a device for delivering a fluidby chemical reaction, comprising: an upper chamber having a seal at alower end; a lower chamber having a port at an upper end, a ring ofteeth at the upper end having the teeth oriented towards the seal of theupper chamber, and a piston at a lower end; and a fluid chamber havingthe piston at an upper end; wherein the upper chamber moves axiallyrelative to the lower chamber; and wherein the piston moves in responseto pressure generated in the lower chamber such that the volume of thereaction chamber increases and the volume of the fluid chamberdecreases.

The piston may include a head and a balloon that communicates with theport. The ring of teeth may surround the port. The upper chamber maytravel within a barrel of the device. Sometimes, the upper chamber isthe lower end of a plunger. The plunger may include a pressure lock thatcooperates with a top end of the device to lock the upper chamber inplace after being depressed. Alternatively, the top end of the devicecan include a pressure lock that cooperates with a top surface of theupper chamber to lock the upper chamber in place when moved sufficientlytowards the lower chamber.

The fluid chamber may contain a high-viscosity fluid having a viscosityof at least 40 centipoise. The upper chamber may contain a solvent. Thelower chamber may contain at least two chemical reagents that react witheach other to generate a gas. Sometimes, the upper chamber, the lowerchamber, and the fluid chamber are separate pieces that are joinedtogether to make the device. In yet other embodiments, either the upperchamber or the lower chamber contains an encapsulated reagent.

Also described herein is a device for delivering a fluid by chemicalreaction, comprising: an upper chamber; a lower chamber having a pistonat a lower end; a fluid chamber having the piston at an upper end; and aplunger comprising a shaft that runs through the upper chamber, astopper at a lower end of the shaft, and a thumbrest at an upper end ofthe shaft, the stopper cooperating with a seat to separate the upperchamber and the lower chamber; wherein pulling the plunger causes thestopper to separate from the seat and create fluid communication betweenthe upper chamber and the lower chamber; and wherein the piston moves inresponse to pressure generated in the lower chamber such that the volumeof the reaction chamber increases and the volume of the fluid chamberdecreases.

The fluid chamber may contain a high-viscosity fluid having a viscosityof at least 40 centipoise. The upper chamber may contain a solvent. Thelower chamber may contain at least two chemical reagents that react witheach other to generate a gas. Sometimes, the upper chamber, the lowerchamber, and the fluid chamber are separate pieces that are joinedtogether to make the device. In yet other embodiments, either the upperchamber or the lower chamber contains an encapsulated reagent.

The present disclosure also relates to a device for delivering a fluidby chemical reaction, comprising: a reaction chamber divided by abarrier into a first compartment and a second compartment, the firstcompartment containing at least two dry chemical reagents that can reactwith each other to generate a gas, and the second compartment containinga solvent; and a fluid chamber having an outlet; wherein fluid in thefluid chamber exits through the outlet in response to pressure generatedin the reaction chamber.

The pressure generated in the reaction chamber may act on a piston inthe fluid chamber to cause fluid to exit through the outlet.

In some embodiments, the reaction chamber is formed from a sidewall, thefluid chamber is formed from a sidewall, and the reaction chamber andthe fluid chamber are fluidly connected at a first end of the device.

In other embodiments, the reaction chamber includes a flexible wall,proximate to the fluid chamber; and wherein the fluid chamber is formedfrom a flexible sidewall, such that pressure generated in the reactionchamber causes the flexible wall to expand and compress the flexiblesidewall of the fluid chamber, causing fluid to exit through the outlet.

The reaction chamber and the fluid chamber may be surrounded by ahousing. Sometimes, the reaction chamber and the fluid chamber areside-by-side in the housing. In other embodiments, a needle extends froma bottom of the housing and is fluidly connected to the outlet of thefluid chamber; and the reaction chamber is located on top of the fluidchamber.

The reaction chamber may be defined by the one-way valve, a sidewall,and the piston, the one-way valve and the sidewall being fixed relativeto each other such that the volume of the reaction chamber changes onlythrough movement of the piston.

Also disclosed in various embodiments is a device for dispensing a fluidby chemical reaction, comprising: a reaction chamber having first andsecond ends; a piston at a first end of the reaction chamber, the pistonbeing operative to migrate within the device in response to a pressuregenerated in the reaction chamber; and a one-way valve at the second endof the reaction chamber permitting entry into the reaction chamber.

The reaction chamber may have a volume of at most 1 cm³. The reactionchamber may contain a dry acid powder and a release agent. In particularembodiments, the acid powder is citrate and the release agent is sodiumchloride. Alternatively, the reaction chamber can contain at least oneor at least two chemical reagents that react with each other to generatea gas. Separately, the reaction chamber may further comprise a releaseagent.

The device may further comprise a fluid chamber containing the fluid tobe dispensed, the piston being operative to decrease the volume of thefluid chamber in response to the pressure generated in the reactionchamber. The fluid chamber may contain a high-viscosity fluid having anabsolute viscosity of from about 5 centipoise to about 1000 centipoise,or a viscosity of at least 40 centipoise.

The device may further comprise a reagent chamber on an opposite side ofthe one-way valve. The reagent chamber may contain a solvent and abicarbonate powder dissolved in the solvent. The solvent can comprisewater. The device may further comprise a plunger at an end of thereagent chamber opposite the one-way valve. The plunger may cooperatewith the reagent chamber to lock the plunger in place after beingdepressed.

The piston may be formed from a push surface at the reaction chamber, astopper, and a rod connecting the push surface and the stopper.

The reaction chamber can be defined by the one-way valve, a sidewall,and the piston, the one-way, valve and the sidewall being fixed relativeto each other such that the volume of the reaction chamber changes onlythrough movement of the piston.

Also disclosed in various embodiments is a device for delivering a fluidby chemical reaction, comprising: a barrel which is divided into areagent chamber, a reaction chamber, and a fluid chamber by a one-wayvalve and a piston; and a plunger at one end of the reagent chamber;wherein the one-way valve is located between the reagent chamber and thereaction chamber; and wherein the piston separates the reaction chamberand the fluid chamber, the piston being moveable to change the volumeratio between the reaction chamber and the fluid chamber.

The present disclosure also relates to a device for delivering a fluidby chemical reaction, comprising: a barrel containing a reaction chamberand a fluid chamber which are separated by a moveable piston; and athermal source for heating the reaction chamber.

The reaction chamber may contain at least one chemical reagent thatgenerates a gas upon exposure to heat. The at least one chemical reagentcan be 2,2′-azobisisobutyronitrile. The generated gas can be nitrogengas.

The reaction chamber may have a volume of at most 1 cm³. The fluidchamber may contain a high-viscosity fluid having an absolute viscosityof from about 5 centipoise to about 1000 centipoise, or a viscosity ofat least 40 centipoise.

The present disclosure also describes a device for delivering a fluid bychemical reaction, comprising: a barrel containing a reaction chamberand a fluid chamber which are separated by a moveable piston; and alight source that illuminates the reaction chamber.

The reaction chamber may contain at least one chemical reagent thatgenerates a gas upon exposure to light. The at least one chemicalreagent can be silver chloride.

The reaction chamber may have a volume of at most 1 cm³. The fluidchamber may contain a high-viscosity fluid having an absolute viscosityof from about 5 centipoise to about 1000 centipoise, or a viscosity ofat least 40 centipoise.

Also described herein in various embodiments is a process for deliveringa high-viscosity fluid by chemical reaction, comprising: initiating agas-generating chemical reaction in a reaction chamber of a device, thechamber including a piston; wherein the gas moves the piston into afluid chamber containing the high-viscosity fluid and delivers thehigh-viscosity fluid; and wherein the high-viscosity fluid is deliveredwith a constant pressure versus time profile.

The initiating can be performed by dissolving at least two differentchemical reagents in a solvent. The at least two chemical reagents caninclude a chemical compound having a first dissolution rate and the samechemical compound having a second different dissolution rate. Thedissolution rates can be obtained by changing the surface area of thechemical compound, or by encapsulating the chemical compound with acoating to obtain the different dissolution rate.

The pressure versus time profile may include a burst.

The reaction chamber may contain a dry acid reagent, with a solventcontaining a predissolved bicarbonate being added to the reactionchamber from a reagent chamber on an opposite side of the one-way valveto initiate the reaction. The reaction chamber can further comprise arelease agent, such as sodium chloride. The solvent may comprise water.In embodiments, the dry acid reagent is a citric acid powder or anacetic acid powder. The gas produced may be carbon dioxide.

In other variations, the initiating is performed by exposing at leastone chemical reagent in the reaction chamber to heat or light. The atleast one chemical reagent can be 2,2′-azobisisobutyronitrile. The gasproduced can be nitrogen gas.

The reaction chamber may have a volume of at most 1 cm³. The fluidchamber may contain a high-viscosity fluid having an absolute viscosityof from about 5 centipoise to about 1000 centipoise, or a viscosity ofat least 40 centipoise.

The piston can be formed from a push surface at the reaction chamber, astopper, and a rod connecting the push surface and the stopper.

Also described in embodiments herein is a device for delivering a fluidby chemical reaction, comprising: a barrel containing a reagent chamber,a reaction chamber, and a fluid chamber; wherein the reagent chamber islocated within a push button member at a top end of the barrel; aplunger separating the reagent chamber from the reaction chamber; aspring biased to push the plunger into the reagent chamber when the pushbutton member is depressed; and a piston separating the reaction chamberfrom the fluid chamber, wherein the piston moves in response to pressuregenerated in the reaction chamber.

The push button member can comprise a sidewall closed at an outer end bya contact surface, a lip extending outwards from an inner end of thesidewall, and a sealing member proximate a central portion on anexterior surface of the sidewall.

The barrel may include an interior stop surface that engages the lip ofthe push button member.

The plunger may comprise a central body having lugs extending radiallytherefrom, and a sealing member on an inner end which engages a sidewallof the reaction chamber. The interior surface of the push button membercan include channels for the lugs.

The reaction chamber may be divided into a mixing chamber and an arm byan interior radial surface, the interior radial surface having anorifice, and the piston being located at the end of the arm. The mixingchamber sometimes includes a gas permeable filter covering the orifice.

The barrel can be formed from a first piece and a second piece, thefirst piece including the reagent chamber and the reaction chamber, andthe second piece including the fluid chamber.

Also disclosed in different embodiments is an injection device fordelivering a pharmaceutical fluid to a patient by means of pressureproduced by an internal chemical reaction, comprising: a reagent chamberhaving an activator at an upper end and a one-way valve at a lower end,the one-way valve permitting exit of a reagent from the reagent chamberinto a reaction chamber upon activation; the reaction chamberoperatively connected to the reagent chamber, having means for receivingthe one-way valve at an upper end and a piston at a lower end; and afluid chamber operatively connected to the reaction chamber, havingmeans for receiving the piston at an upper end, wherein the piston movesin response to pressure generated in the reaction chamber such that thevolume of the reaction chamber increases and the volume of the fluidchamber decreases.

BRIEF DESCRIPTION OF THE DRAWINGS

The following is a brief description of the drawings, which arepresented for the purposes of illustrating the exemplary embodimentsdisclosed herein and not for the purposes of limiting the same.

FIG. 1 is a diagram of a chemical reaction that produces a gas formoving a piston within a chamber.

FIG. 2 is a diagram of a first embodiment of a device for delivering afluid by chemical reaction. The chemical reaction here is generated whentwo dry chemical reagents are dissolved in a solvent and react. Thisfigure shows the device in a storage state, where the dry reagents areseparated from the solvent.

FIG. 3 is a diagram showing the device of FIG. 2 after the dry reagentsare combined with the solvent.

FIG. 4 is diagram showing the device of FIG. 2 with the piston beingpushed by gas pressure to deliver the fluid.

FIG. 5 is a diagram showing another exemplary embodiment of a device fordelivering a fluid by chemical reaction of two reagents in a solvent.This device is made in four separate pieces that are joined together toform a combined device similar to that shown in FIG. 2.

FIG. 6 is a diagram of a first embodiment of a device for delivering afluid by chemical reaction. The chemical reaction here is generated whena chemical reagent is exposed to heat. The device includes a thermalsource.

FIG. 7 is a side cross-sectional view of a first exemplary embodiment ofan injection device. This embodiment uses a one-way valve to create twoseparate chambers.

FIG. 8 is a cross-sectional perspective view of the engine in anexemplary embodiment of FIG. 7.

FIG. 9 is a side cross-sectional view of a second exemplary embodimentof an injection device. This embodiment uses a seal to create twoseparate chambers, and a ring of teeth to break the seal.

FIG. 10 is a cross-sectional perspective view of the engine in thesecond exemplary embodiment of FIG. 9.

FIG. 11 is a side cross-sectional view of a third exemplary embodimentof an injection device. In this embodiment, pulling the handle upwards(i.e. away from the barrel of the device) breaks the seal between twoseparate chambers. This figure shows the device prior to pulling thehandle upwards.

FIG. 12 is a cross-sectional perspective view of the engine in the thirdexemplary embodiment of FIG. 11 prior to pulling the handle upwards.

FIG. 13 is a cross-sectional perspective view of the engine in the thirdexemplary embodiment of FIG. 11 after pulling the handle upwards.

FIG. 14 is a side cross-sectional view of an exemplary embodimentshowing the engine using an encapsulated reagent. This figure shows thedevice in a storage state.

FIG. 15 is a side cross-sectional view of the exemplary embodimentshowing the engine using an encapsulated reagent. This figure shows thedevice in a use state.

FIG. 16 is a perspective see-through view of a first exemplaryembodiment of a patch pump that uses a chemical reaction to injectfluid. Here, the engine and the fluid chamber are side-by-side, and bothhave rigid sidewalls.

FIG. 17 is a perspective see-through view of a second exemplaryembodiment of a patch pump that uses a chemical reaction to injectfluid. Here, the engine is on top of the fluid chamber, and both have aflexible wall. The engine expands and presses the fluid chamber. Thisfigure shows the patch pump when the fluid chamber is empty and prior touse.

FIG. 18 is a perspective see-through view of the patch pump of FIG. 17,where the fluid chamber is filled.

FIG. 19 is a side cross-sectional view of another exemplary embodimentof a syringe that uses a gas-generating chemical reaction. Here, astopper is biased by a compression spring to travel through the reagentchamber and ensure its contents are emptied into the reaction chamber.

FIG. 20 is a bottom view showing the interior of the push button memberin the syringe of FIG. 19.

FIG. 21 is a top view of the stopper used in the syringe of FIG. 19.

FIG. 22 is a graph showing the pressure versus time profile for deliveryof silicone oil when different amounts of water are injected into areaction chamber. The y-axis is Gauge Pressure (Pa), and the x-axis isTime (sec). The plot shows results for conditions where three differentamounts of water were used—0.1 mL, 0.25 mL, and 0.5 mL.

FIG. 23 is a graph showing the volume versus time profile for deliveryof 73 cP silicone oil when a release agent (NaCl) is added to thereaction chamber. The y-axis is Volume (ml), and the x-axis is Time(sec).

FIG. 24 is a volume vs. time graph for delivery of a 73 cP siliconefluid in which the use of modifying or mixing bicarbonate morphology isshown: reaction chamber contains 100% as received, 100% freeze-dried,75% as-received/25% freeze dried, or 50% as-received/50% freeze dried.

FIG. 25 is a pressure vs. time graph for delivery of a 73 cP siliconefluid in which the use of modifying or mixing bicarbonate morphology isshown: reaction chamber contains 100% as received, 100% freeze-dried,75% as-received/25% freeze dried, or 50% as-received/50% freeze dried.

FIG. 26 is a normalized pressure vs. time graph delivery of a 73 cPsilicone fluid during an initial time period. The use of modifying ormixing bicarbonate morphology is shown: reaction chamber contains 100%as received, 100% freeze-dried, 75% as-received/25% freeze dried, or 50%as-received/50% freeze dried.

FIG. 27 is a normalized pressure vs. time graph delivery of a 73 cPsilicone fluid during a second time period. The reaction chambercontained bicarbonates with different morphology or mixed morphology:100% as received, 100% freeze-dried, 75% as-received/25% freeze dried,and 50% as-received/50% freeze dried.

FIG. 28 is a volume vs. time graph for delivery of a 73 cP siliconefluid in which the use of reagents with different dissolution rate orstructure is shown. The engine contained either 100% as-received bakingsoda and citric acid powder, 100% alka seltzer adjusted for similarstoichiometric ratio, 75% as-received powders/25% Alka Seltzer, 50%, 25%as-received powders/75% alka seltzer.

FIG. 29 is a pressure vs. time graph for delivery of a 73 cP siliconefluid in which the use of reagents with different dissolution rate orstructure is shown. The engine contained either 100% as-received bakingsoda and citric acid powder, 100% alka seltzer adjusted for similarstoichiometric ratio, 75% as-received powders/25% Alka Seltzer, 50%, 25%as-received powders/75% alka seltzer.

FIG. 30 is a pressure vs. time graph for the delivery of a 1 cP waterfluid in which the use of reagents with different dissolution rate orstructure is shown. The engine contained either 100% as-received bakingsoda and citric acid powder, 100% alka seltzer adjusted for similarstoichiometric ratio, 75% as-received powders/25% Alka Seltzer, 50%, 25%as-received powders/75% alka seltzer.

FIG. 31 is a normalized pressure vs. time graph for delivery of a 73 cPsilicone fluid in which the use of reagents with different dissolutionrate or structure is shown. The engine contained either 100% as-receivedbaking soda and citric acid powder, 100% alka seltzer adjusted forsimilar stoichiometric ratio, 75% as-received powders/25% Alka Seltzer,50%, 25% as-received powders/75% alka seltzer. The pressure isnormalized by normalizing the curves in FIG. 29 to their maximumpressure.

FIG. 32 is a normalized pressure vs. time graph expanding the first 3seconds of FIG. 31.

FIG. 33 is a volume vs. time graph for delivery of a 73 cP siliconefluid in which the reaction chamber contained either sodium bicarbonate(BS), potassium bicarbonate, or a 50/50 mixture.

FIG. 34 is a pressure vs. time graph for the third set of tests;delivery of a 73 cP silicone fluid in which the reaction chambercontained either sodium bicarbonate (BS), potassium bicarbonate, or a50/50 mixture.

FIG. 35 is a reaction rate graph for the third set of tests; delivery ofa 73 cP silicone fluid in which the reaction chamber contained eithersodium bicarbonate (BS), potassium bicarbonate, or a 50/50 mixture.

FIG. 36 is a volume vs. time graph for a fourth set of tests forsilicone oil.

DETAILED DESCRIPTION

Viscosity can be defined in two ways: “kinematic viscosity” or “absoluteviscosity.” Kinematic viscosity is a measure of the resistive flow of afluid under an applied force. The SI unit of kinematic viscosity ismm²/sec, which is 1 centistoke (cSt). Absolute viscosity, sometimescalled dynamic or simple viscosity, is the product of kinematicviscosity and fluid density. The SI unit of absolute viscosity is themillipascal-second (mPa-sec) or centipoise (cP), where 1 cP=1 mPa-sec.

A “protein” is a sequence of amino acids that is of sufficient chainlength to produce a tertiary or quaternary structure. Examples ofproteins include monoclonal antibodies, insulin, human growth hormone,and erythropoietin.

It should be noted that many of the terms used herein are relativeterms. For example, the terms “inlet” and “outlet” are relative to adirection of flow, and should not be construed as requiring a particularorientation or location of the structure. Similarly, the terms “upper”and “lower”, and “top” and “bottom”, are relative to a central point.For example, an upper component is located in one direction from thecentral point and a lower component would be located in the oppositedirection from the central point.

The term “parenteral” refers to a delivery means that is not through thegastrointestinal tract, such as injection or infusion.

The processes of the present disclosure can be used with both manualsyringes or auto-injectors and is not limited to cylindrical geometries.The term “syringe” is used interchangeably to refer to manual syringesand auto-injectors of any size or shape. The term “injection device” isused to refer to any device that can be used to inject the fluid into apatient, including for example syringes and patch pumps.

FIG. 1 illustrates the generation of pressure by a chemical reaction foruse in delivering a pharmaceutical formulation by injection or infusion.Referring to the left hand side of the figures, one or more chemicalreagents 100 are enclosed within a reaction chamber 110. One side of thechamber can move relative to the other sides of the chamber, and acts asa piston 120. The chamber 110 has a first volume prior to the chemicalreaction.

A chemical reaction is then initiated within the chamber, as indicatedby the “RXN” arrow. A gaseous byproduct 130 is generated at some rate,n(t), where n represents moles of gas produced and t represents time.The pressure is proportional to the amount of gaseous byproduct 130generated by the chemical reaction, as seen in Equation (1):

P{t)−[n{t)·T]IV  (1)

In Equation (1), T represents temperature and V represents the volume ofthe chamber 110.

The volume of the chamber 110 remains fixed until the additional forcegenerated by the gas pressure on the piston 120 exceeds that needed topush the fluid through a syringe needle. The necessary force depends onthe mechanical components present in the system, e.g. frictional forcesand mechanical advantages provided by the connector design, the syringeneedle diameter, and the viscosity of the fluid. The viscosity of thefluid can be approximated using the Hagen-Poiseuille equation.

Once the minimum pressure required to move the piston 120 is exceeded,the volume of the reaction chamber 110 begins to increases. The movementof the piston 120 causes delivery of fluid within the syringe to begin.The pressure in the chamber 110 depends on both the rate of reaction andthe rate of volume expansion, as represented by Equation (1).Preferably, sufficient gas is generated to account for the volumeexpansion, while not generating too much excess pressure. This can beaccomplished by controlling the rates of reaction and gas release in thechamber 110.

The pressure build-up from the chemical-reaction produced gaseousbyproduct 130 can be used to push fluid directly adjacent to the piston120 through the syringe. Pressure build-up may also push fluid in anindirect fashion, e.g., by establishing a mechanical contact between thepiston 120 and the fluid, for example by a rod or shaft connecting thepiston 120 to a stopper of a prefilled syringe that contains fluid.

The one or more chemical reagents 100 are selected so that uponreaction, a gaseous byproduct 130 is generated. Suitable chemicalreagents 100 include reagents that react to generate a gaseous byproduct130. For example, citric acid (C₆H₈O₇) or acetic acid (C₂H₄O₂) willreact with sodium bicarbonate (NaHCO₃) to generate carbon dioxide, CO₂,which can be initiated when the two reagents are dissolved in a commonsolvent, such as water. Alternatively, a single reagent may generate agas when triggered by an initiator, such as light, heat, or dissolution.For, example, the single reagent 2,2′-azobisisobutyronitrile (AIBN) canbe decomposed to generate nitrogen gas (N₂) at temperatures of 50°C.-65° C. The chemical reagent(s) are selected so that the chemicalreaction can be easily controlled.

One aspect of the present disclosure is the combination of variouscomponents to result in (i) enough force to deliver a viscous fluid in ashort time period and (ii) in a small package that is compatible withthe intended use, i.e. driving a syringe. In time, size, and in forcemust all come together to achieve the desired injection.

In examples described further herein, an injection device using agas-generating chemical reaction was used to displace fluid having aviscosity greater than 70 centipoise (cP) through a 27 gauge thin-wall(TW) needle in less than 10 seconds. A 27 gauge thin-wall needle has anominal outer diameter of 0.016±0.0005 inches, a nominal inner diameterof 0.010±0.001 inches, and a wall thickness of 0.003 inches. Suchresults are expected to also be obtained with needles having largernominal inner diameters.

The selection of the chemical reagent(s) can be based on differentfactors. One factor is the dissolution rate of the reagent, i.e. therate at which the dry powder form of the reagent dissolves in a liquid.The dissolution rate can be modified by changing the particle size orsurface area of the powder, encapsulating the powder with a coating thatdissolves first, or changes in the solvent quality. Another factor isthe desired pressure versus time profile. The pressure versus timeprofile can be controlled by modifying the kinetics of the reaction. Inthe simplest case, the kinetics of a given reaction will depend onfactors such as the concentration of the reagents, depending on the“order” of the chemical reaction, and the temperature. For many reagents100, including those in which two dry reagents must be mixed, thekinetics will depend on the rate of dissolution. For example, bycombining powders that have two different dissolution rates, thepressure versus time profile can be modified, enabling constant pressureover time or a profile having a burst in pressure at a specified time.Introduction of a catalyst can be used to the same effect.Alternatively, a delivered volume versus time profile can have aconstant slope. The term “constant” refers to the given profile having alinear upward slope over a time period of at least 2 seconds, with anacceptable error of ±15%.

This ability to tune the chemical reaction allows the devices of thepresent disclosure to accommodate different fluids (with varying volumesand/or viscosities), patient needs, or delivery device designs.Additionally, while the chemical reaction proceeds independently of thegeometry of the reaction chamber, the shape of the reaction chamber canaffect how accumulated pressure acts on the piston.

The target pressure level for providing drug delivery may be determinedby the mechanics of the syringe, the viscosity of the fluid, thediameter of the needle, and the desired delivery time. The targetpressure is achieved by selecting the appropriate amount andstoichiometric ratio of reagent, which determines n (moles of gas),along with the appropriate volume of the reaction chamber. Thesolubility of the gas in any liquid present in the reaction chamber,which will not contribute to the pressure, should also be considered.

If desired, a release agent may be present in the reaction chamber toincrease the rate of fluid delivery. When a solvent, such as water, isused to facilitate diffusion and reaction between molecules, thegenerated gas will have some solubility or stability in the solvent. Therelease agent facilitates release of any dissolved gas into the headspace of the chamber. The release agent decreases the solubility of thegas in the solvent. Exemplary release agents include a nucleating agentthat facilitates the nucleation, growth, and release of gas bubbles viaheterogeneous nucleation. An exemplary release agent is sodium chloride(NaCl). The presence of the release agent can increase the overall rateof many chemical reactions by increasing the dissolution rate, which isoften the rate limiting factor for pressure generation for dry (powder)reagents. The release agent may also be considered to be a catalyst.

In particular embodiments, the volume of the reaction chamber is 1 cm³or less. The other components of the device can be dimensioned to matchthe volume of the reaction chamber. A reaction chamber no more than 1cm³ allows enables chemical-reaction delivery of a high-viscosity fluidwith a limited injection space or footprint.

FIG. 2 illustrates one exemplary embodiment of a device (here, asyringe) that can be used to deliver a high-viscosity fluid using achemical reaction between reagents to generate a gas. The syringe 400 isdepicted here in a storage state or a non-depressed state in which thechemical reaction has not yet been initiated. The needle is not includedin this illustration.

The syringe 400 includes a barrel 410 that is formed from a sidewall412, and the interior space is divided into three separate chambers.Beginning at the top end 402 of the barrel, the syringe includes areagent chamber 420, a reaction chamber 430, and a fluid chamber 440.The plunger 470 is inserted into an upper end 422 of the reagentchamber. A one-way valve 450 is present at a lower end 424 of thereagent chamber, forming a radial surface. The one-way valve 450 is alsopresent at the upper end 432 of the reaction chamber. The one-way valve450 is directed to permit material to exit the reagent chamber 420 andto enter the reaction chamber 430. The lower end 434 of the reactionchamber is formed by a piston 460. Finally, the piston 460 is present atthe upper end 442 of the fluid chamber. The orifice 416 of the barrel isat the lower end 444 of the fluid chamber, and at the bottom end 404 ofthe syringe. It should be noted that the one-way valve 450 is fixed inplace and cannot move within the barrel 410. In contrast, the piston 460can move within the barrel in response to pressure. Put another way, thereaction chamber 430 is defined by the one-way valve 450, the barrelsidewall 412, and the piston 460.

The reaction chamber 430 can also be described as having a first end anda second end. The moveable piston 460 is at the first end 434 of thereaction chamber, while the one-way valve 450 is present at the secondend 432 of the reaction chamber. In this illustration, the reactionchamber 430 is directly on one side of the piston 460, and the fluidchamber 440 is directly on the opposite side of the piston.

The reagent chamber 420 contains at least one chemical reagent, asolvent, and/or a release agent. The reaction chamber 430 contains atleast one chemical reagent, a solvent, and/or a release agent. The fluidchamber 440 contains the fluid to be delivered. As depicted here, thereagent chamber 420 contains a solvent 480, the reaction chamber 430contains two different chemical reagents 482, 484 in a dry powder form,and the fluid chamber 440 contains a high-viscosity fluid 486. Again, itshould be noted that this figure is not drawn to scale. The chemicalreagents, as illustrated here, do not fill up the entire volume of thereaction chamber. Instead, a head space 436 is present within thereaction chamber.

In specific embodiments, the reagent chamber contains a bicarbonatewhich has been pre-dissolved in a solvent, and the reaction chambercontains a dry acid powder. It was found that passive mixing of reagentsin the solvent was a problem that would reduce the speed of reaction.Bicarbonate was pre-dissolved, otherwise it was too slow to dissolve andparticipate in the gas generating reaction. In more specificembodiments, potassium bicarbonate was used. It was found that sodiumbicarbonate did not react as quickly. Citrate was used as the dry acidpowder because it was fast-dissolving and fast-reacting. Sodium chloride(NaCl) was included as a dry release agent with the citrate. The sodiumchloride provided nucleation sites to allow the gas to evolve fromsolution more quickly.

Each chamber has a volume, which in the depicted illustration isproportional to the height of the chamber. The reagent chamber 420 has aheight 425, the reaction chamber 430 has a height 435, and the fluidchamber 440 has a height 445. In this non-depressed state, the volume ofthe reaction chamber is sufficient to contain the solvent and the twochemical reagents.

In particular embodiments, the volume of the reaction chamber is 1 cm³or less. The other components of the device can be dimensioned to matchthe volume of the reaction chamber. A reaction chamber no more than 1cm³ allows enables chemical-reaction delivery of a high-viscosity fluidwith a limited injection space or footprint.

In FIG. 3, the plunger 470 has been depressed, i.e. the syringe is in adepressed state. This action causes the one-way valve 450 to be opened,and the solvent 480 enters into the reaction chamber 430 and dissolvesthe two chemical reagents (illustrated now as bubbles in the solvent).After the plunger 470 is depressed and no further pressure is beingexerted on the one-way valve, the one-way valve 450 closes (this figureshows the valve in an open state). In particular embodiments, the barrelsidewall 412 at the lower end 424 of the reagent chamber may containgrooves 414 or is otherwise shaped to capture the plunger 470. Putanother way, the plunger 470 cooperates with the lower end 424 of thereagent chamber 420 to lock the plunger in place after being depressed.

In FIG. 4, the dissolution of the two chemical reagents in the solventhas resulted in the generation of a gas 488 as a byproduct of thechemical reaction. As the amount of gas increases, the pressure exertedon the piston 460 increases until, after reaching a threshold value, thepiston 460 moves downward towards the bottom end 404 of the syringe (asindicated by the arrow). This causes the volume of the reaction chamber430 to increase, and the volume of the fluid chamber 440 to decrease.This results in the high-viscosity fluid 486 in the fluid chamber beingdispensed through the orifice. Put another way, the combined volume ofthe reaction chamber 430 and the fluid chamber remains constant, but thevolume ratio of reaction chamber to fluid chamber 440 will increase asgas is generated in the reaction chamber. Note that the one-way valve450 does not permit the gas 488 to escape from the reaction chamber intothe reagent chamber.

The syringe can provide consistent force when the following elements areproperly controlled: (i) the particle size of the dry powder reagent;(ii) the moisture content of the dry powder reagent; (iii) the mass ofthe reagents and the quantity of release agent; and (iv) the shapeconfiguration of the chambers for consistent filling and packaging.

FIG. 5 illustrates another variation of a device 700 that uses achemical reaction between reagents to generate gas. This illustration isin a storage state. Whereas the barrel of FIG. 2 is shown as being madefrom an integral sidewall, the barrel in the device of FIG. 5 is made ofseveral shorter pieces. This construction can simplify manufacturing andfilling of the various chambers of the overall device. Another largedifference in this variation is that the piston 760 is made up of threedifferent parts: a push surface 762, a rod 764, and a stopper 766.

Beginning at the top of FIG. 5, the reagent chamber 720 is made from afirst piece 726 that has a first sidewall 728 to define the sides of thereagent chamber. The plunger 770 is inserted in the upper end 722 of thepiece to seal that end. The first piece 720 can then be turned upsidedown to fill the reagent chamber 720 with the solvent 780.

A second piece 756 containing the one-way valve 750 can then be joinedto the lower end 724 of the first piece to seal the reagent chamber 720.A second sidewall 758 surrounds the one-way valve. The lower end 724 ofthe first piece and the upper end 752 of the second piece can be joinedusing known means, such as screw threads (e.g. a Luer lock). Asillustrated here, the lower end of the first piece would have internalthreads, while the upper end of the second piece would have the externalthreads.

The third piece 736 is used to form the reaction chamber 730, and isalso formed from a third sidewall 738. The push surface 762 of thepiston is located within the third sidewall 738. After placing thechemical reagents, solvent, and/or release agent upon the push surface,the lower end 754 of the second piece and the upper end 732 of the thirdpiece are joined together. Two reagents 782, 784 are depicted here. Therod 764 of the piston extends down from the push surface 762.

Finally, the fourth piece 746 is used to form the fluid chamber 740.This fourth piece is formed from a fourth sidewall 748 and a conicalwall 749 that tapers to form the orifice 716 from which fluid will beexpelled. The orifice is located at the lower end 744 of the fluidchamber. The fluid chamber can be filled with the fluid to be delivered,and the stopper 766 can then be placed in the fluid chamber. As seenhere, the stopper 766 may include a vent hole 767 so that air can escapefrom the fluid chamber as the stopper is being pushed down to thesurface of the fluid 786 to prevent air from being trapped in the fluidchamber. A cap 768 attached to the lower end of the piston rod 764 canbe used to cover the vent hole 767. Alternatively, the lower end of thepiston rod can be inserted into the vent hole. The lower end 734 of thethird piece and the upper end 742 of the fourth piece are then joinedtogether.

As previously noted, the piston 760 in this variation is formed from thepush surface 762, the rod 764, and the stopper 766 being connectedtogether. An empty volume 790 is thus present between the reactionchamber 730 and the fluid chamber 740. The size of this empty volume canbe varied as desired. For example, it may be useful to make the overalldevice longer so that it can be more easily grasped by the user.Otherwise, this variation operates in the same manner as described abovewith regards to FIGS. 2-4. The push surface portion of the piston actsin the reaction chamber, and the stopper portion of the piston acts inthe fluid chamber. It should also be noted that the push surface, rod,stopper, and optional cap can be one integral piece, or can be separatepieces.

FIG. 6 illustrates an exemplary embodiment of a device (again, asyringe) that can be used to deliver a high-viscosity fluid using achemical reaction initiated by heat to generate a gas. Again, thesyringe 800 is depicted here in a storage state.

The barrel 810 is formed from a sidewall 812 and the interior space isdivided into two separate chambers, a reaction chamber 830 and a fluidchamber 840. The reaction chamber 830 is present at an upper end 802 ofthe syringe. The upper end 832 of the reaction chamber is formed by aradial wall 838. Located within the reaction chamber is a thermal source850 that can be used for heating. The thermal source 850 may be locatedon the radial wall 838 or, as depicted here, on the barrel sidewall 812.

The lower end 834 of the reaction chamber is formed by a piston 860. Thereaction chamber 830 is defined by the radial wall 838, the barrelsidewall 812, and the piston 860. The piston 860 is also present at theupper end 842 of the fluid chamber. The orifice 816 of the barrel is atthe lower end 844 of the fluid chamber, i.e. at the lower end 804 of thesyringe. Again, only the piston 860 portion of the reaction chamber canmove within the barrel 810 in response to pressure. The radial wall 838is fixed in place, and is solid so that gas cannot pass through.

The reaction chamber contains a chemical reagent 882. For example, thechemical reagent can be 2,2′-azobisisobutyronitrile. A head space 836may be present in the reaction chamber. The fluid chamber 840 contains afluid 886.

An activation trigger 852 is present on the syringe, which can be forexample on top near the finger flange 815 or on the external surface 816of the barrel sidewall. When activated, the thermal source 850 generatesheat. The thermal source can be, for example, an infrared light emittingdiode (LED). The chemical reagent 882 is sensitive to heat, andgenerates a gas (here, N2). The pressure generated by the gas causes thepiston 860 to move, expelling the high-viscosity fluid 886 in the fluidchamber 840.

It should be noted again that the piston may alternatively be the pushsurface, rod, and stopper version described in FIG. 5. This version maybe appropriate here as well.

In an alternative embodiment, the thermal source is replaced by a lightsource 854 which can illuminate the reaction chamber 830. The chemicalreagent 884 here is sensitive to light, and generates a gas uponexposure to light. For example, the chemical reagent may be silverchloride (AgCl). The pressure generated by the gas causes the piston tomove, expelling the high-viscosity fluid in the fluid chamber. Thepiston version of FIG. 5 can also be used here if desired.

Any suitable chemical reagent or reagents can be used to generate a gas.For example, bicarbonate will react with acid to form carbon dioxide.Sodium, potassium, and ammonium bicarbonate are examples of suitablebicarbonates. Suitable acids could include acetic acid, citric acid,potassium bitartrate, disodium pyrophosphate, or calcium dihydrogenphosphate. Any gas can be generated by the chemical reaction, such ascarbon dioxide, nitrogen gas, oxygen gas, chlorine gas, etc. Desirably,the generated gas is inert and non-flammable. Metal carbonates, such ascopper carbonate or calcium carbonate, can be decomposed thermally toproduce CO₂ and the corresponding metal oxide. As another example,2,2′-azobisisobutyronitrile (AIBN) can be heated to generate nitrogengas. As yet another example, the reaction of certain enzymes (e.g.yeast) with sugar produces CO2. Some substances readily sublime, goingfrom solid to gas. Such substances include but are not limited tonaphthalene and iodine. Hydrogen peroxide can be decomposed withcatalysts such as enzymes (e.g. catalase) or manganese dioxide toproduce oxygen gas. As another example, silver chloride will decomposeupon exposure to light.

It is contemplated that the high-viscosity fluid to be dispensed usingthe devices of the present disclosure can be a solution, dispersion,suspension, emulsion, etc. The high-viscosity formulation may contain aprotein, such as a monoclonal antibody or some other protein which istherapeutically useful. The protein may have a concentration of fromabout 150 mg/ml to about 500 mg/ml. The high-viscosity fluid may have anabsolute viscosity of from about 5 centipoise to about 1000 centipoise.In other embodiments, the high-viscosity fluid has an absolute viscosityof at least 40 centipoise, or at least 60 centipoise. The high-viscosityfluid may further contain a solvent or non-solvent, such as water,perfluoroalkane solvent, safflower oil, or benzyl benzoate.

FIG. 7 and FIG. 8 are different views of the first exemplary embodimentof an injection device (here, a syringe) that can be used to deliver ahigh-viscosity fluid using a chemical reaction between reagents togenerate a gas. The syringe 300 is depicted here in a storage state or anon-depressed state in which the chemical reaction has not yet beeninitiated. FIG. 7 is a side cross-sectional view, and FIG. 8 is aperspective view of the engine of the syringe.

The syringe 300 includes a barrel 310 whose interior space is dividedinto three separate chambers. Beginning at the top end 302 of thebarrel, the syringe includes an upper chamber 320, a lower chamber 330,and a fluid chamber 340. These three chambers are coaxial, and aredepicted here as having a cylindrical shape. The lower chamber may alsobe considered a reaction chamber.

The plunger 370 is inserted into an upper end 322 of the upper chamber,and the stopper 372 of the plunger travels through only the upperchamber. A one-way valve 350 is present at a lower end 324 of the upperchamber, forming a radial surface. The one-way valve 350 is also presentat the upper end 332 of the lower chamber. The one-way valve 350 isdirected to permit material to exit the upper chamber 320 and to enterthe lower chamber 330. A piston 360 is present at the lower end 334 ofthe lower chamber. The piston 360 is also present at the upper end 342of the fluid chamber. As illustrated here, the piston is formed of atleast two pieces, a push surface 362 that is at the lower end of thelower chamber and a head 366 at the upper end of the fluid chamber. Theneedle 305 is at the lower end 344 of the fluid chamber, and at thebottom end 304 of the syringe. It should be noted that the one-way valve350 is fixed in place and cannot move within the barrel 310, or in otherwords is stationary relative to the barrel. In contrast, the piston 360can move within the barrel in response to pressure. Put another way, thelower chamber 330 is defined by the one-way valve 350, the continuoussidewall 312 of the barrel, and the piston 360.

The lower chamber 330 can also be described as having a first end and asecond end. The moveable piston 360 is at the first end 334 of the lowerchamber, while the one-way valve 350 is present at the second end 332 ofthe lower chamber. In this illustration, the lower chamber 330 isdirectly on one side of the piston 360, and the fluid chamber 340 isdirectly on the opposite side of the piston.

As previously noted, the piston 360 is formed from at least the pushsurface 362 and the head 366. These two pieces can be connected togetherphysically, for example with a rod (not shown) that has the push surfaceand the head on opposite ends. Alternatively, it is also contemplatedthat an incompressible gas could be located between the push surface andthe head. An empty volume 307 would thus be present between the lowerchamber 330 and the fluid chamber 340. The size of this empty volumecould be varied as desired. For example, it may be useful to make theoverall device longer so that it can be more easily grasped by the user.Alternately, as illustrated in another embodiment in FIG. 9 and FIG. 10further herein, the piston may use a balloon that acts as the pushsurface and acts upon the head 366. As yet another variation, the pistonmay be a single piece, with the push surface being on one side of thesingle piece and the head being on the other side of the single piece.

The upper chamber 320 contains at least one chemical reagent or asolvent. The lower chamber 330 contains at least one chemical reagent ora solvent. The fluid chamber 340 contains the fluid to be delivered. Itis generally contemplated that dry reagents will be placed in the lowerchamber, and a wet reagent (i.e. solvent) will be placed in the upperchamber. As depicted here, the upper chamber 320 would contain asolvent, the lower chamber 330 would contain two different chemicalreagents in a dry powder form, and the fluid chamber 340 would contain ahigh-viscosity fluid. The reagent(s) in either chamber may beencapsulated for easier handling during manufacturing. Each chamber hasa volume, which in the depicted illustration is proportional to theheight of the chamber. In this non-depressed state, the volume of thelower chamber is sufficient to contain the solvent and the two chemicalreagents.

When the plunger in the syringe of FIG. 7 and FIG. 8 is depressed, theadditional pressure causes the one-way valve 350 to open, and thesolvent in the upper chamber 320 enters into the lower chamber 330 anddissolves the two chemical reagents. After the plunger 370 issufficiently depressed and no further pressure is being exerted on theone-way valve, the one-way valve 350 closes. As illustrated here, theplunger includes a thumbrest 376 and a pressure lock 378 on the shaft374 which is proximate to the thumbrest. The pressure lock cooperateswith an upper surface 326 of the upper chamber to lock the plunger inplace. The two chemical reagents may react with each other in thesolvent to generate gas in the lower chamber. As the amount of gasincreases, the pressure exerted on the push surface 362 of the piston360 increases until, after reaching a threshold value, the piston 360moves downward towards the bottom end 304 of the syringe. This causesthe volume of the lower chamber 330 to increase, and the volume of thefluid chamber 340 to decrease. This results in the high-viscosity fluidin the fluid chamber being dispensed through the orifice (by the head366). Put another way, the combined volume of the lower chamber 330 andthe fluid chamber remains constant, but the volume ratio of lowerchamber to fluid chamber 340 will increase as gas is generated in thereaction chamber. Note that the one-way valve 350 does not permit thegas to escape from the lower chamber into the upper chamber. Also, thepressure lock 378 on the plunger permits the stopper 372 to act as asecondary backup to the one-way valve 350, and also prevents the plungerfrom being pushed up and out of the upper chamber.

In specific embodiments, the upper chamber contains a bicarbonate whichhas been pre-dissolved in a solvent, and the lower chamber contains adry acid powder. It was found that passive mixing of reagents in thesolvent was a problem that would reduce the speed of reaction.Bicarbonate was pre-dissolved, otherwise it was too slow to dissolve andparticipate in the gas generating reaction. In more specificembodiments, potassium bicarbonate was used. It was found that sodiumbicarbonate did not react as quickly. Citrate was used as the dry acidpowder because it was fast-dissolving and fast-reacting. Sodium chloride(NaCl) was included as a dry release agent with the citrate. The sodiumchloride provided nucleation sites to allow the gas to evolve fromsolution more quickly.

It should be noted that the upper chamber 320, the lower chamber 330,and the fluid chamber 340 are depicted here as being made from separatepieces that are joined together to form the syringe 300. The pieces canbe joined together using methods known in the art. For example, theupper chamber is depicted here as being formed from a sidewall 325having a closed upper end 322 with a port 327 for the plunger. Thestopper 372 of the plunger is connected to the shaft 374. The one-wayvalve 350 is a separate piece which is inserted into the open lower end324 of the upper chamber. The lower chamber is depicted here as beingformed from a sidewall 335 having an open upper end 332 and an openlower end 334. The upper end of the lower chamber and the lower end ofthe upper chamber cooperate to lock together and fix the one-way valvein place. Here, the locking mechanism is a snap fit arrangement, withthe upper end of the lower chamber having the cantilever snap 380 thatincludes an angled surface and a stop surface. The lower end of theupper chamber has the latch 382 that engages the cantilever snap.Similarly, the lower chamber and the fluid chamber are fitted togetherwith a ring-shaped seal.

FIG. 9 and FIG. 10 are different views of an exemplary embodiment of aninjection device of the present disclosure. The syringe 500 is depictedhere in a storage state or a non-depressed state in which the chemicalreaction has not yet been initiated. FIG. 9 is a side cross-sectionalview, and FIG. 10 is a perspective view of the engine of the syringe.

Again, the syringe includes a barrel 510 whose interior space is dividedinto three separate chambers. Beginning at the top end 502 of thebarrel, the syringe includes an upper chamber 520, a lower chamber 530,and a fluid chamber 540. These three chambers are coaxial, and aredepicted here as having a cylindrical shape. The lower chamber 530 mayalso be considered a reaction chamber.

In this embodiment, the upper chamber 520 is a separate piece locatedwithin the barrel 510. The barrel is illustrated here as an outersidewall 512 that surrounds the upper chamber. The upper chamber 520 isillustrated here with an inner sidewall 525 and a top wall 527. A shaft574 and a thumbrest I button 576 extend from the top wall 527 of theupper chamber in the direction away from the barrel. Thus, the upperchamber 520 could also be considered as forming the lower end of aplunger 570. The lower end 524 of the upper chamber is closed off with aseal 528, i.e. a membrane or barrier such that the upper chamber has anenclosed volume. It should be noted that the inner sidewall 525 of theupper chamber travels freely within the outer sidewall 512 of thebarrel. The upper chamber moves axially relative to the lower chamber.

The lower chamber 530 has a port 537 at its upper end 532. A ring 580 ofteeth is also present at the upper end 532. Here, the teeth surround theport. Each tooth 582 is illustrated here as having a triangular shape,with a vertex oriented towards the seal 528 of the upper chamber, andeach tooth is angled inwards towards the axis of the syringe. The term“tooth” is used here generally to refer to any shape that can puncturethe seal of the upper chamber.

A piston 560 is present at the lower end 534 of the lower chamber 530.The piston 560 is also present at the upper end 542 of the fluid chamber540. Here, the piston 560 includes the head 566 and a balloon 568 withinthe lower chamber that communicates with the port 537 in the upper end.Put another way, the balloon acts as a push surface for moving the head.The head 566 may be described as being below or downstream of theballoon 568, or alternatively the balloon 568 can be described as beinglocated between the head 566 and the port 537. The needle 505 is at thelower end 544 of the fluid chamber, and at the bottom end 504 of thesyringe. The balloon is made from a suitably non-reactive material.

The top end 502 of the barrel (i.e. the sidewall) includes a pressurelock 518 that cooperates with the top surface 526 of the upper chamberto lock the upper chamber 520 in place when moved sufficiently towardsthe lower chamber 530. The upper chamber 520 is illustrated hereextending out of the outer sidewall 512. The top end 526 of the outersidewall is shaped to act as the cantilever snap, and the top surface526 of the upper chamber acts as the latch.

Alternatively, the top end of the device may be formed as depicted inFIG. 8, with the pressure lock on the shaft proximate to the thumbrestand cooperating with the top end of the device.

As previously described, it is generally contemplated that dry reagentswill be placed in the lower chamber 530, and a wet reagent (i.e.solvent) will be placed in the upper chamber 520. Again, the reagent(s)in either chamber may be encapsulated for easier handling duringmanufacturing. More specifically, it is contemplated that the reagentsin the lower chamber would be located within the balloon 568.

During operation of the syringe of FIG. 9 and FIG. 10, pushing thebutton 576 downwards causes the upper chamber 520 to move into thebarrel towards the ring 580 of teeth. The pressure of the upper chamberagainst the ring of teeth causes the seal 528 to break, releasing thecontents of the upper chamber into the lower chamber 530. Here, it iscontemplated that the gas-generating reaction occurs within the balloon568. The increased gas pressure causes the balloon to inflate (i.e.lengthen). This pushes the head 566 towards the bottom end 504 of thesyringe (note the upper chamber will not be pushed out of the barrel dueto the pressure lock). This again causes the volume of the lower chamber530 to increase, and the volume of the fluid chamber 540 to decrease,i.e. the volume ratio of lower chamber to fluid chamber to increase.

There is an empty volume 507 present between the balloon 568 and thehead 566. An incompressible gas could be located in this empty volume.The size of this empty volume can be varied as desired, for example tomake the overall device longer.

Again, the upper chamber 520, the lower chamber 530, and the fluidchamber 540 can be made from separate pieces that are joined together toform the syringe. It should be noted that FIG. 10 is made from fivepieces (590, 592, 594, 596, and 598), with the additional pieces beingdue to the addition of the balloon in the lower chamber and to the upperchamber being separate from the outer sidewall. However, this embodimentcould still be made from fewer pieces as in FIG. 8. For example, theballoon could be located close to the ring of teeth.

FIG. 11, FIG. 12, and FIG. 13 are different views of a third exemplaryembodiment of an injection device of the present disclosure. In thisembodiment, the mixing of the chemical reagents is initiated by pullingthe plunger handle away from the barrel, rather than towards the barrelas in the embodiments of FIGS. 7-10. FIG. 11 is a side cross-sectionalview of the syringe in a storage state. FIG. 12 is a perspective view ofthe engine of the syringe in a storage state. FIG. 13 is a perspectiveview of the engine of the syringe in its operating state, i.e. when thehandle is pulled upwards away from the barrel of the syringe.

The syringe 700′ includes a barrel 710′ whose interior space is dividedinto three separate chambers. Beginning at the top end 702′ of thebarrel, the syringe includes an upper chamber 720′, a lower chamber730′, and a fluid chamber 740′. These three chambers are coaxial, andare depicted here as having a cylindrical shape. The lower chamber mayalso be considered a reaction chamber.

In this embodiment, the plunger 770′ is inserted into an upper end 722′of the upper chamber. In the storage state, the shaft 774′ runs throughthe upper chamber from the lower end 724′ to the upper end 722′ andthrough the upper surface 726′ of the upper chamber. A seal 728′ ispresent at the top end where the shaft exits the upper chamber. Thethumbrest 776′ at the upper end of the shaft is outside of the upperchamber. The stopper 772′ at the lower end of the shaft cooperates witha seat 716′ within the barrel such that the upper chamber has anenclosed volume. For example, the top surface of the stopper may have alarger diameter than the bottom surface of the stopper. The seat 716′may be considered as being at the lower end 724′ of the upper chamber,and also as being at the upper end 732′ of the lower chamber.

A piston 760′ is present at the lower end 734′ of the lower chamber. Thepiston 760′ is also present at the upper end 742′ of the fluid chamber740′. As illustrated here, the piston 760′ is formed of at least twopieces, a push surface 762′ and a head 766′. An empty volume 707′ can bepresent. Other aspects of this piston are similar to that described inFIG. 8. Again, the piston can move within the barrel in response topressure. The lower chamber 730′ can also be described as being definedby the seat 716, the continuous sidewall 712′ of the barrel, and thepiston 760′. The needle 705′ is at the lower end 744′ of the fluidchamber, and at the bottom end 704′ of the syringe.

During operation of the syringe of FIGS. 11-13, it is generallycontemplated that dry reagents will be placed in the lower chamber 730′,and a wet reagent (i.e. solvent) will be placed in the upper chamber720′, as previously described. Referring now to FIG. 11, pulling theplunger 770′ upwards (i.e. away from the barrel) causes the stopper 772′to separate from the seat 716′. This creates fluid communication betweenthe upper chamber 720′ and the lower chamber 730′. The reagent in theupper chamber travels around the stopper into the lower chamber(reference number 717′). The gas-generating reaction then occurs in thelower chamber 730′. The gas pressure pushes the piston 760′ towards thebottom end 704′ of the syringe. In other words, the volume of the lowerchamber increases, and the volume of the fluid chamber decreases, i.e.the volume ratio of lower chamber to fluid chamber increases. Oneadditional advantage to this embodiment is that once the reagents begingenerating gas, the pressure created will continue to push the plunger710′ further out of the upper chamber, helping to push more reagent outof the upper chamber 720′ into the lower chamber 730′, furthering thegeneration of gas.

Referring to FIG. 12, the barrel 710′ is depicted as being made up ofthree different pieces 790′, 792′, 794′. A seal 738′ is also locatedbetween the pieces that make up the lower chamber and the fluid chamber.

FIG. 14 and FIG. 15 are cross-sectional views of one aspect of anotherexemplary embodiment of the injection device of the present disclosure.In this embodiment, the liquid reagent (i.e. the solvent) isencapsulated in a capsule is broken when a button is pressed. FIG. 14shows this engine before the button is pressed. FIG. 15 shows the engineafter the button is pressed.

Referring first to FIG. 14, the top end 1002 of the syringe 1000 isshown. A reaction chamber 1030 contains a capsule 1038 and dryreagent(s) 1039. Here, the capsule rests on a ledge 1031 above the dryreagent(s). A push surface 1062 of a piston 1060 is present at the lowerend of the reaction chamber. The head 1066 of the piston is alsovisible, and is at the upper end 1042 of the fluid chamber 1040. Abutton/plunger 1070 is located above the capsule. A seal 1026 may bepresent between the button 1070 and the capsule 1038. The barrelcontains a safety snap 1019 to prevent the button from falling out ofthe end of the barrel.

If desired, the portion of the reaction chamber containing the capsulecould be considered an upper chamber, and the portion of the reactionchamber containing the dry reagent(s) could be considered a lowerchamber.

Referring now to FIG. 15, when the button 1070 is pushed, the capsule1038 is broken, causing the solvent and the dry reagent(s) to mix. Thisgenerates a gas that pushes the piston 1060 downward and ejects fluidfrom the fluid chamber 1040. Pushing the button subsequently engages apressure lock 1018 that prevents the button from being pushed upwards bythe gas pressure.

The embodiments of the figures described above have been illustrated asauto-injectors. Auto-injectors are typically held in the user's hand,have a cylindrical form factor, and have a relatively quick injectiontime of one second to 30 seconds. It should be noted that the conceptsembodied in the above-described figures could also be applied to othertypes of injection devices, such as patch pumps. Generally, a patch pumphas a flatter form factor compared to a syringe, and also has thedelivery time is typically greater than 30 seconds. Advantages to usinga chemical gas-generating reaction in a patch pump include the smallvolume required, flexibility in the form/shape, and the ability tocontrol the delivery rate.

FIG. 16 is an illustration of a typical patch pump 1200. The patch pumpincludes a reaction chamber 1230 and a fluid chamber 1240 located withina housing 1280. As shown here, the reaction chamber and the fluidchamber are located side-by-side, though this can vary as desired. Thereaction chamber 1230 is formed from a sidewall 1235. The fluid chamber1240 is also formed from a sidewall 1245. The reaction chamber and thefluid chamber are fluidly connected by a passage 1208 at a first end1202 of the device. The fluid chamber 1240 includes an outlet 1246 thatis connected to a needle 1205 located at opposite second end 1204 of thehousing. The needle 1205 extends from the bottom 1206 of the housing.

The reaction chamber is divided into a first compartment and a secondcompartment by a barrier (not visible). In this regard, the firstcompartment is analogous to the lower chamber, and the second chamber isanalogous to the upper chamber previously described.

The reaction chamber can be considered as an engine that causes fluid inthe fluid chamber to be ejected. In this regard, it is contemplated thata gas-generating chemical reaction can be initiated by breaking the sealbetween the first compartment and the second compartment. The barriercould be broken, for example, by bending or snapping the patch pumphousing, or by pushing at a designated location on the housing. Thiscauses the reagents to mix. Because the desired delivery time is longer,the speed at which the chemicals are mixed is not as great a concern.The pressure builds up and can act on a piston (not visible) in thefluid chamber, causing fluid to exit through the outlet. It iscontemplated that the volume of the reaction chamber and the fluidchamber do not change significantly in this embodiment.

FIG. 17 and FIG. 18 are perspective see-through views of anotherexemplary embodiment of a patch pump. In this embodiment, the reactionchamber/engine 1230 is located on top of the fluid chamber 1240. Theneedle 1205 extends from the bottom 1206 of the housing 1280. In thisembodiment, the reaction chamber 1230 includes a flexible wall 1235. Thefluid chamber 1240 also includes a flexible sidewall 1245. The flexiblewall of the reaction chamber is proximate to the flexible sidewall ofthe fluid chamber. The reaction chamber and the fluid chamber are notfluidly connected to each other in this embodiment. Instead, it iscontemplated that as gas is generated in the reaction chamber, thereaction chamber will expand in volume. The flexible wall 1235 of thereaction chamber will compress the flexible sidewall 1245 of the fluidchamber, causing fluid in the fluid chamber to exit through the outlet1246. Put another way, the volume ratio of reaction chamber to fluidchamber increases over time as the reaction chamber inflates and thefluid chamber dispenses fluid. It should be noted that a relativelyconstant volume is required in this embodiment, so that the increasingvolume of the reaction chamber causes compression of the fluid chamber.This can be accomplished, for example, by including a rigid backing onthe opposite side of the reaction chamber from the flexible wall, or bymaking the housing from a relatively rigid material.

FIG. 19 illustrates another exemplary embodiment of a device (here, asyringe) that can be used to deliver a high-viscosity fluid using achemical reaction between reagents to generate a gas. The syringe 1300is depicted here in a storage state or a non-depressed state in whichthe chemical reaction has not yet been initiated. The needle is notincluded in this illustration.

The syringe 1300 includes a barrel 1310 whose interior space is dividedinto three separate chambers. Beginning at the top end 1302 of thebarrel, the syringe includes a reagent chamber 1320, a reaction chamber1330, and a fluid chamber 1340. These three chambers are coaxial, andare depicted here as having a cylindrical shape. In this embodiment, thebarrel of the syringe is formed from two different pieces. The firstpiece 1380 includes a sidewall 1312 that forms the reaction chamber andprovides a space 1313 for the reagent chamber. The sidewall is open atthe top end 1302 for a push button described further herein. The fluidchamber is made from a second piece 1390 which can be attached to thefirst piece.

The sidewall 1312 of the first piece includes an interior radial surface1314 that divides the first piece into an upper space 1313 and thereaction chamber 1330. The reaction chamber has a smaller inner diameter1325 compared to the inner diameter 1315 of the upper space.

The reagent chamber is located in a separate push button member 1350that is located within the upper space 1313 of the first piece andextends through the top end 1302 of the barrel. As illustrated here, thepush button member is formed from a sidewall 1352 which is closed at theouter end 1351 by a contact surface 1354, and which forms an interiorvolume into which reagent is placed (i.e. the reagent chamber). Asealing member 1356 (shown here as an O-ring) is proximate a centralportion on the exterior surface 1355 of the sidewall, and engages thesidewall 1312 in the upper space. The inner end 1353 of the sidewallincludes a lip 1358 extending outwards from the sidewall. The lipengages an interior stop surface 1316 on the barrel. The reagent chamberis depicted as containing a solvent 1306 in which bicarbonate isdissolved.

A plunger 1370 is located between the reagent chamber 1320 and thereaction chamber 1330. The plunger 1370 is located at the inner end 1324of the reagent chamber. The plunger includes a central body 1372 havinglugs 1374 extending radially therefrom (here shown as four lugs, thoughthe number can vary). The lugs also engage the lip 1358 of the pushbutton member when the syringe is in its storage state. The lugs areshaped with an angular surface 1376, such that the plunger 1370 rotateswhen the push button member 1350 is depressed. An inner end 1373 of thecentral body includes a sealing member 1378 (shown here as an O-ring)which engages the sidewall in the reaction chamber.

The reaction chamber 1330 includes a top end 1332 and a bottom end 1334.Another interior radial surface 1336 is located at a central location inthe reaction chamber, separating the reaction chamber into a mixingchamber 1335 and an arm/fitting 1333, with the mixing chamber 1335 beingproximate the reagent chamber 1320 or the top end 1332. An orifice 1331within the interior radial surface leads to the arm fitting 1333 whichengages the second piece 1390 containing the fluid chamber 1340. Thepiston 1360 is located at the bottom end of the reaction chamber, i.e.at the end of the arm 1333. Located within the reaction chamber is a dryreagent 1308. Here, the dry reagent is citrate, and is in the form of atablet. The dry reagent is depicted here as being located upon theinterior radial surface, i.e. in the mixing chamber. A gas-permeable Iliquid-solid impermeable filter 1337 may be present across the orifice.The filter keeps any dry solid reagent and a liquid inside the mixingchamber to improve mixing.

In addition, a compression spring 1395 is located within the mixingchamber, extending from the interior radial surface 1336 to the innerend 1373 of the plunger. A compression spring stores energy whencompressed (i.e. is longer when no load is applied to it). Because thepush button member 1350 and the plunger 1370 are fixed in place, thecompression spring 1395 is compressed in the storage state. It should benoted that here, the spring surrounds the dry reagent. It is alsocontemplated, in alternate embodiments, that the dry reagent is attachedto the inner end 1373 of the plunger.

Finally, the piston 1360 is also present at the upper end 1342 of thefluid chamber. Again, the piston 1360 can move within the barrel inresponse to pressure generated in the reaction chamber. The piston canalso be described as having a push surface 1362 and a stopper 1364.

The sealing member 1378 of the plunger separates the liquid reagent inthe reagent chamber 1320 from the dry reagent in the reaction chamber1330. While liquid 1306 is illustrated as being present in the pushbutton member, it is also possible that liquid is present in the barrelin the upper space 1313 around the plunger.

When the push button member 1350 is depressed (down to the interiorradial surface 1316), the plunger 1370 is rotated. This causes the lugs1374 of the plunger to disengage from the lip 1358 of the push buttonmember. In addition, it is contemplated that the push button member,once depressed, cannot be retracted from the barrel. This can be done,for example, using a stop surface near the outer end of the barrel (notshown).

When the plunger 1370 is no longer held in place by the push buttonmember, the compression spring extends and pushes the plunger 1370 intothe push button member 1350. It is contemplated that the compressionspring is sized so that the plunger travels completely through the pushbutton member, but will not push through the contact surface 1354 of thepush button member. The liquid 1306 present in the reagent chamber fallsinto the reaction chamber and contacts the dry reagent 1308. Themovement of the plunger into the push button member is intended to causecomplete emptying of the contents of the reagent chamber into thereaction chamber. This mechanism can also provide forceful mixing of thewet reagent with the dry reagent, either induced by the spring action,initial chemical action, or both.

In some alternate embodiments, the spring also pushes at least some ofthe dry reagent into the reagent chamber (i.e. the interior volume ofthe push button member). For example, the dry reagent could be attachedto the inner end 1373 of the plunger, and driven upwards by the spring.

FIG. 20 is a bottom view illustrating the interior of the push buttonmember. As seen here, the interior surface 1357 of the sidewall formingthe push button member includes four channels 1359 through which thelugs of the plunger can travel. FIG. 21 is a top view of the plunger1370, showing the central body 1372 and the lugs 1374, which can travelin the channels of the push button member. Comparing these two figures,the outer circle of FIG. 20 is the lip 1358 of the push button memberand has an outer diameter 1361. The inner diameter 1363 of the pushbutton member is interrupted by the four channels. The dotted circleindicates the outer diameter 1365 of the sidewall exterior surface 1355.The central body of the plunger has a diameter 1375 which is less thanthe inner diameter 1363 of the push button member, with the lugs fittinginto the channels. This permits the plunger to push the liquid in thepush button member out and around the central body. It should be notedthat the channels do not need to be straight, as illustrated here. Forexample, the channels may be angled to one side, i.e. twist in a helicalmanner. This might be desirable to add turbulence to the liquid reagentand improve mixing.

The combination of the solvent with bicarbonate and the citrate in thereaction chamber 1330 causes gas 1309 to be generated. It should benoted that due to the movement of the plunger, the reagent chamber couldnow be considered to be part of the reaction chamber. In addition, itshould be noted that the dry reagent 1308 in FIG. 19 could be consideredas restricting access to the orifice 1331. Upon dissolution, the orificeis clear and gas can enter the bottom end 1334 of the reaction chamber.

Once a threshold pressure is reached, the piston 1360 travels throughthe fluid chamber 1340, ejecting fluid from the syringe. The needle 1305of the syringe is visible in this figure.

In some alternate contemplated embodiments, the diameter of the plungerincluding the lugs is less than the inner diameter 1363 of the pushbutton member. In other words, channels are not needed on the innersidewall of the push button member. In such embodiments, the barrelsidewall would provide a surface that holds the plunger in place untilthe push button is depressed to rotate the plunger. The shape andmovement of the plunger would then cause turbulence in the liquid as thewet reagent flowed past the lugs into the reaction chamber. It is alsocontemplated that a stem could be attached to the plunger that extendsinto the reagent chamber, or put another way, the stem is attached tothe outer end of the plunger. The stem may be shaped to cause turbulenceand improve mixing.

It is also contemplated that the speed of the injection could beadjusted by the user. One way of doing this would be to control thespeed at which the dry reagent and a wet reagent are mixed. This wouldadjust the speed of the gas-generating chemical reaction, and thereforethe speed at which the force that pushes the piston is generated. Thiscould be accomplished, for example, by adjusting the size of the openingbetween the reagent chamber and the reaction chamber. For example, anadjustable aperture could be placed beneath the plunger. The aperturewould have a minimum size (to accommodate the spring), but couldotherwise be adjusted. Another way of adjusting the speed of theinjection would be to control the size of the reaction chamber. Thiswould adjust the pressure generated by the chemical reaction (becausepressure is force per area). For example, the sidewall of the reactionchamber could move inwards or outwards as desired to change the volumeof the reaction chamber. Alternately, the interior radial surface 1336could include an adjustable aperture to change the size of the orifice1331 and the rate at which gas can enter the bottom end 1334 of thereaction chamber and push on the piston 1360. Both of these methodscould be controlled by a dial on the syringe, which could mechanicallyadjust the speed of injection as desired by the user. It is possiblethat this would allow “on-the-fly” adjustment of the speed of injection.

It is also contemplated that a gas-permeable liquid-solid impermeablefilter may be present that separates the piston from the lower chamberin the injection devices described herein. In this regard, the drypowder has been found in some situations to stick to the sides of thechamber. When the piston moves, remaining solvent falls below the levelof the powder, such that further chemical reaction does not occur. It isbelieved that the filter should keep any dry solid reagent and liquidwithin the lower chamber to improve mixing.

Suitable materials for the injection devices of the present disclosureare known in the art, as are methods for making the injection devices.

The gas-generating chemical reaction used to generate force “on demand”,as opposed to springs, which only store energy when compressed. Mostautoinjectors hold a spring in a compressed position during “on theshelf” storage, causing parts to fatigue and to form over time. Anotheralternative to compressing the spring in manufacturing is to provide acocking mechanism that compresses the spring prior to use. This addsanother step to the process for using the spring-driven device. Inaddition, physically disabled users may have difficulty performing thecocking step. For example, many users of protein drugs are arthritic, orhave other conditions that limit their physical abilities. The forceneeded to activate the gas-generating chemical reaction can be far lessthan that required to activate a spring-driven device or to cock thespring in a spring-driven device. In addition, springs have a linearenergy profile. The force provided by the gas-generating chemicalreaction can be non-linear and non-logarithmic. The speed of thechemical reaction can be controlled by (i) adjusting the particle sizeof the dry reagent; (ii) changing the particle shape of the dry reagent;(iii) adjusting the packing of the dry reagent; (iv) using mixing assistdevices; and/or (v) altering the shape of the reaction chamber where thereagents are mixed.

It should be noted that silicone oil is often added to the barrel of thesyringe to reduce the release force (due to static friction) required tomove the piston within the barrel. Protein drugs and other drugs can benegatively impacted by contact with silicone oil. Siliconization hasalso been associated with protein aggregation. The forces generated bythe chemical reaction obviate the need for application of silicone oilto the barrel of the syringe. In other words, no silicone oil is presentwithin the barrel of the syringe.

When a solvent is used to form a medium for a chemical reaction betweenchemical reagents, any suitable solvent may be selected. Exemplarysolvents include aqueous solvents such as water or saline; alcohols suchas ethanol or isopropanol; ketones such as methyl ethyl ketone oracetone; carboxylic acids such as acetic acid; or mixtures of thesesolvents. A surfactant may be added to the solvent to reduce the surfacetension. This may aid in improving mixing and the subsequent chemicalreaction.

The following examples are for purposes of further illustrating thepresent disclosure. The examples are merely illustrative and are notintended to limit processes or devices made in accordance with thedisclosure to the materials, conditions, or process parameters set forththerein.

Example 1

A test rig was used for carrying out experiments. A standard prefilledsyringe was filled with 1 ml fluid. A prefilled syringe was fitted witha 19 mm long and 27 gauge TW needle and stopped with a standard stopper.This syringe acted as the fluid chamber. Connected to the prefilledsyringe was a reaction chamber syringe. A green piston rod and a pushsurface were used to apply force from the chemical reaction to thestopper. A one-way pressure valve was used to allow injection of solventfrom a second “injector” syringe that acted as the reagent chamber. Theset-up was clamped into the test fixture shown. A graduated pipette wasused to measure the volume delivered versus time.

Two fluids were tested, water (1 cP) and silicone oil (73 cP). Waterserved as the low-viscosity fluid, silicone oil served as thehigh-viscosity fluid. One of these two fluids was added to the prefilledsyringe depending on the experiment. To the reaction chamber syringe wasadded 400 mg NaHCO₃ and 300 mg citric acid, as dry powders. The injectorsyringe was filled with either 0.1 ml, 0.25 ml, or 0.5 ml water. Thewater was injected into the reaction syringe (the volume of the reactionsyringe was adjusted based on the volume to be delivered by the injectorsyringe). The delivered volume versus time and total delivery time weremeasured. The pressure was calculated using the Hagen-Poiseuilleequation and assumed there was 0.6 lb frictional force between thestopper and the prefilled syringe. Alternatively, the force on theprefilled syringe was determined by placing a load cell at the exit. Theresults are shown in Table 1 and were based on a minimum of at leastthree runs.

Injector Syringe Time to Deliver Time to Deliver 1 ml silicone (mlwater) 1 ml water (sec) oil (sec) 0.1 5  24 ± 9.0 0.25 4.5 ± 0.5 16.38 ±4.62  0.5   4 ± 1.0 9.5 ± 0.5 1.0 8.89 ± 0.19 2.0  6.5 ± 0.79 3.0 5.58 ±0.12 4.0 6.54 ± 0.05

The chemical reaction syringe provided delivery of 1 ml water from theprefilled syringe in 5 seconds. The delivery time for the higherviscosity fluid depended on the volume of water injected from theinjector syringe. Surprisingly, the delivery time was faster when thevolume of water was greater. This was surprising because water, whichdoes not participate in the reaction, served to dilute the reagents.Reaction kinetics, the production of CO₂, decrease as the concentrationof reagents decreases. Thus, it was expected that a greater quantity ofinjected water would decrease the concentration and increase thedelivery time due to slower production of CO₂. The results indicate theimportance of the dissolution kinetics, which is the rate limiting stepin this reaction. The dissolution was faster for higher volumes ofwater. Using 0.5 ml of water, high viscosity fluid can be delivered in 9seconds.

FIG. 22 is a graph showing the pressure versus time profile for deliveryof silicone oil when 0.1 ml (triangle), 0.25 ml (square), and 0.5 ml(diamond) of water was injected into the reaction chamber. This graphshows that a nearly constant pressure versus time profile could beobtained after a ramp-up period, although the impact of volume expansiondominated at longer times. These pressure versus time profiles were notexponential. A constant pressure versus time profile may allow forslower, even delivery of a high-viscosity drug, as opposed to a suddenexponential burst near the end of a delivery cycle.

Example 2

Sodium chloride (NaCl) was used to enhance the release of gaseous CO₂from the reaction solution in the reaction chamber, accelerating theincrease in pressure. In control experiments, citric acid and NaHCO₃were placed in the reaction syringe. A solution of 1.15 M NaHCO₃ inwater was injected into the reaction syringe from the injector syringe.The empty volume in the reaction syringe was kept constant through allexperiments. In experiments demonstrating the concept, NaCl was added tothe reaction syringe. The chemical reaction was used to deliver 1 ml ofwater or silicone oil from the prefilled syringe. The delivered volumeversus time and total delivery time were measured. The pressure wascalculated using the Hagen-Poiseuille equation and assumed there was a0.6 lb frictional force between the prefilled plunger and the syringe.Note that bicarbonate was present in the water injected into thereaction syringe, so that gas could be generated even if solidbicarbonate was not present in the reaction syringe itself. The resultsare shown in Table 2.

TABLE 2 Reagents in Reaction Injection Time to Time to Syringe (mg)Syringe Deliver 1 Deliver 1 Solid Citric (mL) 1.15M mL water mL siliconeNo NaHCO₃ Acid NaCl aq. NaHCO₃ (sec) oil (sec) 1 350 304 0 0.5 1.38 ±0.05  8.3 ± 0.8 2 350 304 121 0.5 1.69 ± 0.03  7 ± 1 3 50 76 0 0.5 4 134 50 76 121 0.5 4.9 ± 0.6 11 5 0 38 0 0.5 24 ± 1  41 ± 7 6 0 38 121 0.59 ± 2 20.5 ± 0.5Salt served to significantly enhance the delivery rate, particularly forsystems that used smaller amounts of reagent. A high viscosity fluidcould be delivered in 6 to 8 seconds using the chemical reaction. Thisis significantly faster than what can be achieved with standardauto-injectors that employ mechanical springs.

FIG. 23 shows the delivered volume versus time profile for experimentNos. 5 and 6 of Table 2. A high viscosity fluid was delivered in 20seconds using a system having a footprint of less than 1 cm³. Thedelivery rate (i.e. slope) was also relatively constant. The smallfootprint enables a variety of useful devices.

Example 3

Several different reagents were screened to determine, how the pressureversus time profile could be modified. Generally, reagents with twodifferent dissolution rates were created by combining NaHCO₃ with twodifferent surface areas. High surface area NaHCO₃ was produced by freezedrying a 1.15 M solution; this material had a faster dissolution ratethan as-received NaHCO₃ powder.

Reagents

The following reagents were used: as-received baking soda (NaHCO₃),citric acid, freeze-dried baking soda, Alka-Seltzer, or as-receivedpotassium bicarbonate (KHCO₃). The as-received baking soda was alsotested as a powder, or in a tablet form. The tablet form had a decreasedsurface area.

The freeze-dried baking soda was formulated by preparing 125 ml ofsaturated baking soda aqueous solution (1.1 SM). The solution was pouredinto a 250 ml crystallization dish and covered with a Kimwipe. Thesolution was placed in a freeze dryer and was ramped down to −40° C. andheld for two hours. The temperature remained at −40° C., and a vacuumwas applied at 150 millitorrs (mTorr) for 48 hours. [0181] Alka-Seltzertablets (Effervescent Antacid & Pain Relief by Kroger) were broken upusing a mortar and pestle into a coarse powder.

Baking soda tablets were prepared by pouring 400 mg of as-receivedbaking soda powder in a die to produce a tablet with a 1 cm diameter.The die was swirled around to move the powder to give an even depthacross the 1 cm. The die was placed in a press and held at 13 tonspressure for 1 minute. Tablets weighing 40 mg and 100 mg were brokenfrom the 400 mg tablet.

The Apparatus and Plan

The previously described test rig was used. The 3 ml injection syringewas filled with 0.5 ml of de-ionized water. The 10 ml reaction syringewas connected to the injection syringe by luer locks and a valve, andthen clamped down tightly in the apparatus. A load cell was attached tothe plunger rod so the reaction syringe plunger presses on it during thetest. This recorded the applied force from the reaction while displacingthe fluid in the prefilled syringe.

The fluid from the prefilled syringe was displaced into a graduatedsyringe which was video recorded. This observed the change in volume ofthe fluid over time. The fluids were water (1 cP) or silicone oil (73cP), which were displaced through a 27 gauge thin-walled prefilledsyringe and had a volume of 1 milliliter (ml).

Two measurements were acquired while during each test: the force on theprefilled syringe using a load cell and the change in volume of theprefilled syringe by measuring the dispensed volume with time. Theaverage volume vs. time curve was plotted to show how each reactionchanged the volume in the prefilled syringe. The pressure vs. time curveusing the Hagen-Poiseuille equation was provided by calculating the flowrate from the volume vs. time curve. To account for the friction in theprefilled syringe, 94,219 Pa was added (which is equivalent to 0.6 lb).This calculated the pressure inside the prefilled syringe (3 mm radius)so the hydraulic equation was used (P₁A₁=P₂A₂) to calculate the pressureinside the reaction syringe (6.75 mm diameter). This was used to checkthe measurement made by the load cell.

Another pressure vs. time curve was produced by using the force in theload cell measurement and dividing by the area of the reaction plunger.This has been shown to provide much cleaner and reproducible data thanthe calculation by Hagen-Poiseuille.

To see how the pressure changed with volume, pressure vs. volume curveswere produced. The pressures used were those calculated by the load cellmeasurements. The reaction volume was calculated using the change ofvolume in the prefilled syringe. The volume of the reaction syringe (VR)could be determined from the dispensed volume in the prefilled syringe(Vp) at time t.

Finally, the reaction rate while dispensing the fluid was found by usingthe ideal gas law where PR is the pressure calculated from the loadcell, VR is the volume of the reaction syringe, R is the universal gasconstant (8.314 Jmol⁻¹K⁻¹), and T is the temperature, 298K.

The Tests

The baseline formulation was 400 mg of baking soda, 304 mg of citricacid, and 0.5 ml of de-ionized water as described in Example 1. Thisformulation produces 4.76×10-3 moles of CO₂ assuming 100% yield. Theingredients of all tests were formulated to produce the same 4.76×10-3moles of CO₂ assuming 100% yield. Four sets of tests were performed.

The first set used as-received baking soda (BSAR) and freeze-driedbaking soda (BSFD). Their relative amounts were varied in increments of25%. 304 mg citric acid was also included in each formulation. Table 3Aprovides the target masses of the baking soda for these tests.

TABLE 3A Target Mass [mg] Test BSAR BSFD 100% BSAR 400 0  75% BSAR 300100  50% BSAR 200 200  25% BSAR 100 300 100% BSFD 0 400

The second set used as-received baking soda and Alka-Seltzer. The amountof as-received baking soda was varied in increments of 25%. Thestoichiometric amount of citric acid was added. Alka-Seltzer is onlyapproximately 90% baking soda/citric acid. Therefore, the total mass ofAlka-Seltzer added was adjusted to obtain the required mass of bakingsoda/citric acid. Table 3B provides the target masses of each ingredientfor these tests.

TABLE 3B Target Weight [mg] Test Baking Soda Citric Acid Alka-Seltzer100% BSCA 400 304 0  75% BSCA 300 228 196  50% BSCA 200 152 392  25%BSCA 100 76 586 100% Alka-Seltzer 0 0 777

The third set used as-received baking soda and as-received potassiumbicarbonate. The mass of citric acid was maintained at 304 mg throughoutthe tests. Due to the heavy molar mass of potassium bicarbonate (100.1g/mol as opposed to baking soda's 84.0 g/mol), more mass is required togenerate the same moles of CO₂. Table 3C provides the target masses (inmg) of each ingredient for these tests.

TABLE 3C Test Baking Soda Potassium Bicarbonate 100% BS 400 0  50% BS200 239 100% KHCO3 0 477

The fourth set used the baking soda tablets. The stoichiometric amountof citric acid was used. No other reagents were added. Table 3D providesthe target masses (in mg) of each ingredient for these tests.

TABLE 3D Test Baking Soda Tablet Citric Acid 400BS-304CA 400 304100BS-76CA 100 76  40BS-30CA 40 30

Results of the Tests

First Set: As-Received Baking Soda (BSAR) and Freeze-Dried Baking Soda(BSFD).

The freeze-dried baking soda powder appeared coarse relative to theas-received baking soda powder. It was also less dense; 400 mg of thefreeze-dried powder occupied 2 ml in the reaction syringe, whereas theas-received powder only occupied 0.5 ml. Due to the volume of material,the smaller volume of water (0.5 ml) could not come into contact withall of the freeze-dried baking soda. There was solid freeze-dried bakingsoda after each experiment. Only silicone oil in the prefilled syringewas tested.

In addition to the four test formulations described above, a fifthformulation was run where the freeze-dried sample was inserted first. Itwas followed by the citric acid and then the as-received powder. It waslabeled as “50% BSAR Second”. This formulation permitted the injectedwater to come into contact first with the freeze-dried powder, thencontact and dissolve the citric acid and the as-received powder. Thetime needed to displace 1 ml of the silicone oil is listed in Table 3E.

TABLE 3E Formulation Time (sec) 100% BSAR 10  75% BSAR 13  50% BSAR 11 50% BSAR Second 22 100% BSFD 14

The volume vs. time graph is seen in FIG. 24. It appeared that the 100%freeze-dried powder was initially faster than the 100% as-receivedpowder but slowed over time. The as-received powder took 10 seconds todisplace 1 ml, and the freeze-dried powder took 14 seconds. As expected,the trials with mixed amounts were found to have times between the twoextremes.

The pressure vs. time graph is given in FIG. 25. The formulations with100% BSAR showed a maximum pressures nearly 100,000 Pa higher than thosewith 100% BSFD. In comparison, using “75% BSAR” gave a faster pressureincrease and slower decay. For ease of comparison, the pressures werenormalized and plotted in FIG. 26 and FIG. 27 (two different timeperiods).

The 100% BSAR had an initial slow reaction rate compared to the 75% BSARand 50% BSAR formulations. This suggests the freeze-dried baking soda(BSFD) dissolves and reacts faster, and this is seen in FIG. 26.However, FIG. 25 shows that as the freeze-dried baking soda contentincreases, a lower maximum reaction pressure is obtained. It wasobserved that 200 mg of the freeze-dried baking soda occupies 1 ml ofspace, so the 0.5 ml of de-ionized water cannot contact all of thefreeze-dried powder before the generated gas moves the plunger, leavingthe dry powder behind stuck on the side of the chamber. Put another way,not all of the freeze-dried baking soda can be reacted, resulting inless CO₂ production. It was estimated for the 100% BSFD trial that onlya quarter of the reagent dissolved.

In the 50% BSAR Second trial, when the freeze-dried baking soda wasadded first followed by the citric acid and as-received baking soda,much of the powder remained solid, resulting in a lower pressure. Thelow initial reaction was most likely caused by the 0.5 ml of waterdiffusing through the 1 ml of freeze-dried baking soda powder beforereaching and dissolving the citric acid. Surprisingly, this test was theclosest of the trials in this set to providing a constant pressureprofile.

The maximum pressure obtained was at approximately 0.8 ml CO₂ volume forthe 50% BSAR and 75% BSAR formulations. These formulations also had thefastest rate in the pressure vs. time graphs (see FIG. 26). Theremaining formulations had maximum pressures at approximately 1.2 mlCO₂.

Interestingly, when looking at FIG. 27, the “50% BSAR Second” showed adistinct pressure vs. time profile (Pa/s in FIG. 27), but hadapproximately the same pressure vs. volume profile as the 100% BSFD.Referring back to Table 3E, it took approximately 8 seconds longer forthe “50% BSAR Second” to displace the 1 ml of silicone oil, so itspressure curve is “drawn out” relative to the 100% BSFD, and it had adifferent flow rate. It is unclear why this occurred if the pressure vs.volume curves are the same. Other experiments for this trial failed dueto leaking or clogging, and it is possible the pressure profile wascaused by increased friction in the prefilled syringe.

Table 3F shows the reaction rates fitted to y=ax²+bx.

TABLE 3F Formulation First Term (a) Second Term (b) 100% BSAR 0 5 × 10⁻⁵ 75% BSAR 0 4 × 10⁻⁵  50% BSAR 0 4 × 10⁻⁵  50% BSAR Second −5 × 10⁻⁷ 2 ×10⁻⁵ 100% BSFD −1 × 10⁻⁶ 2 × 10⁻⁵The 100% BSAR, 75% BSAR, and 50% BSAR curves have approximately the samelinear reaction rate. The “50% BSAR Second” forms a second orderpolynomial. The “100% BSFD” appears to be parametric; it has the samelinear rate as 100% BSAR and the other two, and then the slope suddenlydecreases after 5 seconds and converges with “50% BSAR Second.”

It is believed that the second order reaction rates are caused by lossof material and not the rate of reaction itself. In the “100% BSFD”trial, the freeze-dried baking soda had a volume of 2 ml. When the 0.5ml of water was injected, there was plenty of material to dissolve andreact. After 5 seconds, the total reaction volume had opened to 3.27 ml.The syringe had opened up far enough that the water was no longer incontact with the solid freeze-dried baking soda (stuck to the side ofthe chamber). All that could react was what had been dissolved, and thisslowed the rate of reaction. The same was true for the “50% BSARSecond”, except it had to diffuse through 1 ml of the freeze-driedbaking soda before dissolving the citric acid, resulting in a slowerreaction altogether.

Second Set: As-Received Baking Soda and Alka-Seltzer.

The volume vs. time graph is seen in FIG. 28 for silicone oil, and inFIG. 29 for water as the injected fluids respectively. The time neededto displace 1 ml of each fluid is listed in Table 3G. the error in timemeasurement is estimated to be half a second.

TABLE 3G Time (sec) Formulation Silicone Water 100% BSCA   11 ± 0.95 3 75% BSCA 14.78 ± 1.35 3.2  50% BSCA  12.5 ± 2.12 2.27 ± 0.47  25% BSCA10.11 ± 1.02 3 100% Alka-Seltzer 11 2

The times for displacement of water are difficult to compare becausethey are all within one second of each other. The volume profiles for100% BSCA, 25% BSCA, and 100% Atka-Seltzer had the fastest times todisplace 1 ml of silicone oil. The 100% BSCA appeared to start slowlyand then speed up. The 50% BSCA and 75% BSCA were found to have theslowest times. They appeared to slow down as the displacement proceeded.

The pressure vs. time graph is given in FIG. 30 for silicone oil, and inFIG. 31 for water as the injected fluids respectively. The 100% BSCA hadthe slowest initial pressure rise. This was expected, since Alka-Seltzeris formulated to allow fast diffusion of water into the tablet. The 75%BSCA and 50% BSCA had the second and third greatest maximum pressure,respectively, for silicone oil. However, these two formulations took thelongest to displace 1 ml of silicone oil. Their pressures also had theslowest decay. This is most likely due to increased friction in thesyringe.

The curves in FIG. 31 for water are within a reasonable error of eachother. However, they were greater than the estimated pressures byHagen-Poiseuille, which calculated the maximum pressure to be 51,000 Paby the 100% Alka-Seltzer formulation. High friction was not observedduring testing. It is not known why there was a difference in thepressure measured by the load cell and the theoretical pressurecalculated by Hagen-Poiseuille.

Normalized pressure vs. time graphs are provided for silicone oil inFIG. 32, with the first 3 seconds expanded in FIG. 33. The pressuredecay rate for silicone oil is provided in Table 3H.

TABLE 3H Formulation Decay Rate (Pa/s) 100% BSCA 6,854  75% BSCA 4,373 50% BSCA 3,963  25% BSCA 9,380 100% Alka-Seltzer 10,695

For silicone oil, the 100% BSCA and the 75% BSCA had the same normalizedpressure increase, but different decays. As explained above, the 75%BSCA may have undergone more friction causing the change in volume toslow and hold pressure longer. The same was true for the 50% BSCA, whichhad the same decay as 75% BSCA. Surprisingly, the pressure increase for50% BSCA fit just between 100% BSCA and 100% Alka-Seltzer. This mayindicate that friction does not affect the pressure increase. The 100%Alka-Seltzer and 25% BSCA had the same pressure profiles with thefastest pressure increase and fastest decay. The 100% BSCA also appearedto have the same decay as these two formulations.

For water, it was found that higher ratios of Alka-Seltzer to BSCAresulted in relatively less pressure decay. The 100% Alka Seltzer had afast pressure increase but quickly decayed along with 100% BSCA” and 75%BSCA. However, 25% BSCA and 50% BSCA had fast pressure increase and lesspressure decay than the other formulations.

For silicone oil, the 100% Alka-Seltzer, 50% BSCA, and 75% BSCA allpeaked at approximately 1.2 ml of CO₂ volume. The 25% BSCA peaked atapproximately 0.8 ml. The 100% BSCA did not reach maximum pressure untilapproximately 1.6 ml. This was slightly different than the “100% BSAR”in the first set of tests, which used the exact same formulation butreached its maximum pressure at a CO₂ volume of 1.2 ml.

Table 31 shows the reaction rates for CO2 production during injection ofsilicone oil fitted to y=ax²+bx.

TABLE 3I Formulations First Term (a) Second Term (b) 100% BSCA 0 4 ×10⁻⁵  75% BSCA 0 3 × 10⁻⁵  50% BSCA 0 3 × 10⁻⁵  25% BSCA 0 4 × 10⁻⁵ 100%Alka-Seltzer −2 × 10⁻⁶ 6 × 10⁻⁵

All formulations except 100% Alka-Seltzer formed linear reaction ratesfor silicone oil. The high friction in the prefilled syringe used totest 75% BSCA and 50% BSCA caused a high pressure, which may havereduced the reaction rate to 3×10⁻⁵ mol/s. The 100% BSCA and 25% BSCAhad the same reaction rate at 4×10⁻⁵ mol/sec. 100% Alka-Seltzer resultedin a second order polynomial. It initially had the same reaction rate asthe other formulations, but the slope decreased in the last few seconds.When the reaction was finished, the solution was much thicker than theother formulations.

The 100% BSCA was slightly slower than the previous experiment withfreeze-dried baking soda, 100% BSAR (see Table 3F), by 1×10⁻⁵ mol/sec.This may have caused the slower time to displace the silicone andpossibly the maximum pressure at a greater CO₂ volume at 1.6 ml.

Third Set: As-Received Baking Soda and as-Received PotassiumBicarbonate.

The volume vs. time graph is seen in FIG. 34, for silicone oil. The timeneeded to displace 1 ml of each fluid is listed in Table 3J.

TABLE 3J Formulation Time (sec) 100% BS 8.00  50% BS 8.00 100% KHC036.33

The 100% KHCO₃ was the fastest to displace the 1 ml of silicone at 6.33seconds. The 100% BS and 50% BS displaced the same volume at a time of8.00 seconds.

The pressure vs. time graph is given in FIG. 35. The pressure decay ratefor silicone oil is provided in Table 3K.

TABLE 3K Formulation Pressure Decay (Pa/sec) 100% BS 6,017  50% BS 7,657100% KHC03 11,004The 100% BS formulation only reached a maximum pressure of approximately250,000 Pa, while the other two formulations had a maximum pressure ofapproximately 300,000 Pa. The 100% KHCO₃ and 50% BS formulations (eachcontaining potassium bicarbonate) continued increasing in pressure for afew seconds after the 100% BS reached its maximum. The 50% BSformulation initially had less pressure as expected but was able tomaintain a higher pressure after 6 seconds compared to the 100% KHCO₃.The results showed that using a mixture of sodium and potassiumbicarbonate can produce higher pressures and slow decays.

The 100% BS had a peak pressure somewhere between 0.6 and 1.8 ml of CO₂.The curves for 50% BS and 100% KHCO₃ were very different from the otherpressure vs. volume graphs previously seen herein. Instead of peaking atapproximately 1.2 ml of CO₂ volume and decaying, they tended to continueincreasing in pressure at greater CO₂ volumes. The 50% BS and 100% KHC03formulations peaked at approximately 2.0 and 3.2 ml of CO₂ volume,respectively.

A reaction rate graph is given in FIG. 36 for silicone oil, showing thetotal number of moles CO₂ produced over time. Table 3L shows thereaction rates fitted to y=bx.

TABLE 3L Formulation Rate (mol/sec) 100% BS 5 × 10−0  50% BS 9 × 10−0100% KHC03 1 × 10−4They appeared to be linear reaction rates with 100% BS at 5×10⁻⁵ mol/sec(the same rate from the experiments above). Using 100% potassiumbicarbonate had twice the rate as baking soda, although it appeared thatthe reaction rate started to decrease at approximately 4 seconds.

Fourth Set: Baking Soda Tablets.

The volume vs. time graph is seen in FIG. 37 for silicone oil. The timeneeded to displace 1 ml of each silicone oil or water is listed in Table3M.

TABLE 3M Time (sec) Baking Soda Tablet (mg) Silicone Water 400 42 25.67100 104 78 40 247 296

For both silicone oil and water, using 400 mg and 100 mg baking sodatablets and the stoichiometric citric acid resulted in nearly straightlines. Packing the baking soda into dense tablets significantlydecreased reaction rates, and thus increased injection times, relativeto other baking soda experiments. Table 3N shows the reaction ratesfitted to y=ax²+bx.

TABLE 3N Silicone Oil Water First Second Formulations Term (a) SecondTerm (b) First Term (a) Term (b) 400BS 0 4 × 10⁻⁶ 3 × 10⁻⁸ 2 × 10⁻⁷100BS 0 7 × 10⁻⁷ N/A N/A  40BS −4 × 10⁻¹⁰ 2 × 10⁻⁷ N/A N/AFor silicone oil, the 400 mg BS tablet showed the linear reaction rateas 4×10⁻⁶ mol/sec. The 100 mg baking soda tablet was linear for almost87 seconds until it suddenly stopped producing gaseous CO₂. The reactionrate for the 40 mg tablet was a second order polynomial and very slow.It reached a total of 2×10⁻⁵ moles CO₂ and stayed steady with somefluctuation possibly caused by the CO₂ moving in and out of solution.Due to the small reaction rate in water, only the 400 mg tablet wasused.

The results of Example 3 showed the ability to create different pressureversus time profiles when the dissolution kinetics are modified.

Example 4

The test rig was used to test silicone oil and a 27 gauge thin-wallneedle. The stoichiometric reaction and results are shown in Table 4below.

TABLE 4 Reagents in Injection Time to Reaction Syringe (mL) Deliver 1 mLSyringe (mg) Saturated silicone Citric Acid NaCl KHCO₃ oil (sec) 140 2000.5 8

Example 5

The prototype test device illustrated in FIG. 19 was tested usingsilicone oil. A pre-filled syringe acted as the fluid chamber from whichfluid was ejected. Next, a connector was used to join the pre-filledsyringe with the reaction chamber. The reaction chamber included amixing. A piece of filter paper was placed inside the reaction chamberto cover the orifice to the arm. A spring was then placed inside themixing chamber. Next, a plunger was used to separate the dry reagent inthe reaction chamber from the wet liquid. The next piece was the pushbutton, which included an interior volume for the liquid reagent. Thepush button included a hole (not visible) that was used to fill thevolume with liquid reagent. A screw was used to fill the hole in thepush button. A cap was fitted over the push button to provide structuralsupport, and also surrounds a portion of the reaction chamber. Finally,a thumb press was placed on top of the cap for ease of pressing. Boththe reagent chamber and the reaction chamber were completely filled withliquid solution and dry powder, respectively.

The syringe was tested in both the vertical position (reagent chamberabove reaction chamber) and the horizontal position (the two chambersside-by-side). The reagents and results are shown in Table 5 below.

TABLE 5 Reagents in Reagent Time to Reaction Chamber (mL) Deliver 1 mLChamber (mg) Saturated silicone Orientation Citric Acid NaCl KHCO₃ oil(sec) Vertical 250 200 0.75 8.5 Horizontal 250 200 0.75 17

Assuming adequate mixing, the potassium bicarbonate is the limitingreactant, with citric acid at an excess of 89 mg. This assumption wasfound to be incorrect because liquid was found in the top chamber andpowder was found in the bottom chamber when disassembled. When thesyringe was laid in a horizontal position, and the chambers werecompletely filled, the silicone oil was displaced in 17 seconds. Thisillustrates that the device can work in any orientation. This is helpfulfor permitting patients to inject into their abdomen, thigh, or arm,which are the most common locations for self-injection.

It was noted that the push button was more difficult to press. It isbelieved that the mechanical design can be improved to solve thisproblem.

The devices and methods of the present disclosure have been describedwith reference to exemplary embodiments. Obviously, modifications andalterations will occur to others upon reading and understanding thepreceding detailed description. It is intended that the presentdisclosure be construed as including all such modifications andalterations insofar as they come within the scope of the appended claimsor the equivalents thereof.

1. A device for delivering a fluid by chemical reaction, comprising: areagent chamber having a plunger at an upper end and a one-way valve ata lower end, the one-way valve permitting exit from the reagent chamber;a reaction chamber having the one-way valve at an upper end and a pistonat a lower end; and a fluid chamber having the piston at an upper end,wherein the piston moves in response to pressure generated in thereaction chamber such that the volume of the reaction chamber increasesand the volume of the fluid chamber decreases; wherein the reactionchamber contains a dry acid powder and a release agent.
 2. (canceled) 3.A device for delivering a fluid by chemical reaction, comprising: abarrel containing a reaction chamber and a fluid chamber which areseparated by a moveable piston; and a thermal source for heating thereaction chamber or a light source that illuminates the reactionchamber.
 4. The device of claim 3, wherein the reaction chamber containsat least one chemical reagent that generates a gas upon exposure tolight.
 5. A process for delivering a high-viscosity fluid by chemicalreaction, comprising: initiating a gas-generating chemical reaction in areaction chamber of a device, the chamber including a piston; whereinthe gas moves the piston into a fluid chamber containing thehigh-viscosity fluid and delivers the high-viscosity fluid; and whereinthe high-viscosity fluid is delivered with a constant pressure versustime profile.
 6. A device for delivering a fluid by chemical reaction,comprising: a barrel containing a reagent chamber, a reaction chamber,and a fluid chamber; wherein the reagent chamber is located within apush button member at a top end of the barrel; a plunger separating thereagent chamber from the reaction chamber; a spring biased to push theplunger into the reagent chamber when the push button member isdepressed; and a piston separating the reaction chamber from the fluidchamber, wherein the piston moves in response to pressure generated inthe reaction chamber.
 7. The device of claim 6, wherein the push buttonmember comprises a sidewall closed at an outer end by a contact surface,a lip extending outwards from an inner end of the sidewall, and asealing member proximate a central portion on an exterior surface of thesidewall.
 8. The device of claim 6, wherein the plunger comprises acentral body having lugs extending radially therefrom, and a sealingmember on an inner end which engages a sidewall of the reaction chamber.9. The device of claim 8, wherein an interior surface of the push buttonmember includes channels for the lugs.
 10. The device of claim 6,wherein the reaction chamber is divided into a mixing chamber and an armby the interior radial surface, the interior radial surface having anorifice, and the piston being located at the end of the arm.
 11. Thedevice of claim 9, wherein the mixing chamber includes a gas permeablefilter covering the orifice.
 12. A device for delivering a fluid bychemical reaction, comprising: an upper chamber having a seal at a lowerend; a lower chamber having a port at an upper end, a ring of teeth atthe upper end having the teeth oriented towards the seal of the upperchamber, and a piston at a lower end; and a fluid chamber having thepiston at an upper end; wherein the upper chamber moves axially relativeto the lower chamber; and wherein the piston moves in response topressure generated in the lower chamber such that the volume of thereaction chamber increases and the volume of the fluid chamberdecreases.
 13. The device of claim 12, wherein the piston includes ahead and a balloon that communicates with the port.
 14. The device ofclaim 12, wherein the ring of teeth surround the port. 15-16. (canceled)17. The device of claim 16, wherein the plunger includes a pressure lockthat cooperates with a top end of the device to lock the upper chamberin place after being depressed. 18-21. (canceled)
 22. The device ofclaim 16, wherein the upper chamber, the lower chamber, and the fluidchamber are separate pieces that are joined together to make the device.23. A device for delivering a fluid by chemical reaction, comprising: anupper chamber; a lower chamber having a piston at a lower end; a fluidchamber having the piston at an upper end; and a plunger comprising ashaft that runs through the upper chamber, a stopper at a lower end ofthe shaft, and a thumbrest at an upper end of the shaft, the stoppercooperating with a seat to separate the upper chamber and the lowerchamber; wherein pulling the plunger causes the stopper to separate fromthe seat and create fluid communication between the upper chamber andthe lower chamber; and wherein the piston moves in response to pressuregenerated in the lower chamber such that the volume of the reactionchamber increases and the volume of the fluid chamber decreases. 24-26.(canceled)
 27. The device of claim 23, wherein the upper chamber, thelower chamber, and the fluid chamber are separate pieces that are joinedtogether to make the device.
 28. (canceled) 29-35. (canceled) 36-42.(canceled)
 43. The device of claim 1, wherein the upper chamber, thelower chamber, and the fluid chamber are cylindrical and are coaxial.44-45. (canceled)